RARE DISEASE
CHARGE syndrome
CHARGE syndrome
CHARGE syndrome
Synonyms: CHARGE association, Coloboma-heart defects-atresia choanae-retardation of growth and development-genitourinary problems-ear abnormalities syndrome, Hall-Hittner syndrome
Synonyms: CHARGE association, Coloboma-heart defects-atresia choanae-retardation of growth and development-genitourinary problems-ear abnormalities syndrome, Hall-Hittner syndrome
Synonyms: CHARGE association, Coloboma-heart defects-atresia choanae-retardation of growth and development-genitourinary problems-ear abnormalities syndrome, Hall-Hittner syndrome
Drug discovery
1
drug
With orphan designation
Overview
CHARGE syndrome is a multisystem genetic disorder caused by CHD7 gene mutations, characterized by coloboma, heart defects, choanal atresia, growth/developmental delays, genital hypoplasia, and ear anomalies. It involves cranial nerve dysfunction, sensory deficits (hearing/vision loss), and complex medical needs requiring multidisciplinary care. Prevalence is ~1:8,500–1:15,000 live births, with significant morbidity due to life-threatening congenital anomalies and lifelong developmental challenges [1][2][7][16].
Therapies
Surgical interventions: Repair of choanal atresia, cardiac defects, and cleft anomalies [6][15][19].
Multidisciplinary therapies: Physical, occupational, and speech-language therapy for motor/sensory deficits; cochlear implants or hearing aids for auditory loss [3][5][13][20].
Medical management: Hormone replacement (hypogonadism), feeding support (gastrostomy), and scoliosis monitoring [4][6][11][18].
Categories: rare cardiac malformations, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare immunological diseases, rare infertility disorders, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare renal diseases, rare surgical maxillo-facial diseases, rare transplant-related disorders, rare urogenital diseases
Research Papers
224 drug discovery papers about CHARGE syndrome. Recent publications:
224 drug discovery papers about CHARGE syndrome. Recent publications:
categories:
Small molecules
cell therapies
2026-06-18 | Cochlear Implantation and Hearing Rehabilitation in CHARGE Syndrome: Expanding Clinical Knowledge and Outcomes.
Characterize patients with CHARGE syndrome (CS) undergoing cochlear implantation (CI) and evaluate factors influencing surgical approaches and outcomes. Retrospective study. Quaternary pediatric referral center. Fifty-five patients with CS aged ≤21 years who underwent CI. Demographic, audiologic, radiologic, operative, and postoperative data were reviewed. Outcomes included audiologic performance, device use, communication modality, and the presence of facial nerve stimulation (FNS). Surgical feasibility, anatomic characteristics, and auditory outcomes. Fifty-five patients underwent CI, representing 67 ears. The cohort was 62% male, and 91% had neurodevelopmental impairment. Complete electrode insertion was achieved in 81% of ears (54/67), partial insertion in 5% (3/67), and insertion data were unavailable in 15% (10/67). Perimodiolar electrodes were used in 57% of ears. Imaging demonstrated cochlear nerve aplasia or hypoplasia in 54% of implanted ears and cochlear aperture stenosis in 25%. At analysis, 49% of patients were active CI users, while 27% had discontinued use. Audiologic threshold improvement was observed in 47% of patients, and overall clinical benefit was identified in 64% based on combined audiologic and functional measures. Ipsilateral facial nerve stimulation occurred in 15% of implanted ears; among these, 60% remained active users, while 40% discontinued CI use due to FNS unresponsive to reprogramming. CI is feasible and can provide meaningful benefit in patients with CS despite complex anatomic and neurodevelopmental challenges. These findings support an individualized approach to CI candidacy and offer practical guidance for surgical planning and family counseling regarding expected outcomes.
2026-06-04 | CHARGE Syndrome with Athymia Diagnosed by Newborn Screening and Treated with Cord Blood Transplantation: A Case Report
Background CHARGE syndrome is caused by pathogenic variants in the CHD7 gene and is characterized by coloboma, congenital heart defects, choanal atresia, growth retardation/developmental delay, genital hypoplasia, and ear anomalies with hearing loss. CHARGE syndrome with athymia can present with complete absence of the thymus, leading to T cell deficiency and a clinical phenotype of severe combined immunodeficiency (SCID). Early therapeutic intervention is required after diagnosis. Thymic transplantation is the curative treatment; however, when access is limited, hematopoietic stem cell transplantation (HSCT) may be an alternative. In Japan, reports of cord blood transplantation for CHARGE syndrome with athymia are limited, and cases diagnosed and treated before infectious complications through newborn screening (NBS) are extremely rare. Case A male infant was born at 41 weeks’ gestation, weighing 3,632 g. Expanded NBS at day 6 revealed T cell receptor excision circle (TREC) 0 copies, reported on day 16. Positive-pressure management, cessation of breastfeeding, antifungal and anti-CMV prophylaxis, and immunoglobulin replacement were promptly initiated. Genetic testing identified a known frameshift variant in CHD7, and together with imaging findings of thymic aplasia, the patient was diagnosed with CHARGE syndrome with athymia. On day 30, he underwent aortic arch repair for coarctation of the aorta. On day 66, he received a 7/8 HLA allele–matched cord blood transplant without conditioning. T cells appeared in peripheral blood on day 14 post-transplant. At 1 month, he developed stage 2 skin graft versus host disease (GVHD), currently managed with adjustment of immunosuppressive therapy; no other transplant-related complications or infections have occurred. Conclusion Although long-term outcomes after HSCT require further follow-up, this case demonstrates that diagnosis of CHARGE syndrome with athymia by NBS prior to infectious complications enabled early appropriate supportive care and treatment planning, which likely contributed to a reduced risk of transplant-related mortality.
2026-05-06 | Cochlear Implantation in Patients With CHARGE Syndrome: A Systematic Review and Meta-Analysis.
Currently, there are limited large studies exploring cochlear implantation (CI) outcomes in patients with CHARGE syndrome. We aim to evaluate preoperative and postoperative speech and auditory outcomes in patients with CHARGE syndrome undergoing CI from a review of published single-center studies. PubMed, Scopus, and CINAHL. A total of 15 studies were included for analysis, encompassing 85 CHARGE patients with a total of 99 implanted ears. Extracted data included demographic information, study characteristics, and speech perception and auditory outcomes. Pooled analyses of scaled auditory outcome measures were performed using standardized mean differences (SMDs). Risk of bias was assessed using the Joanna Briggs Critical Appraisal Checklist to evaluate the quality and validity of included studies. This meta-analysis demonstrates significant global postoperative improvement in auditory outcomes for patients with CHARGE syndrome who underwent CI. Meta-analyzed data showed a significant increase in Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) scores following CI, with an estimated overall pre/post mean difference of 11.9 ( P = 0.036), and a significant increase in categories of auditory performance (CAP) scores following CI, with an estimated overall pre/post mean difference of 2.9 ( P = 0.004). Despite the complexity of inner ear malformations in this population, these findings contribute to the growing body of evidence supporting the use of CIs in CHARGE patients.
2026-02-17 | Lacrimal drainage system involvement in CHARGE syndrome: a two-case report.
CHARGE syndrome is a rare multisystem disorder, with ocular colobomas being the most frequent ophthalmic manifestation. Lacrimal drainage system anomalies are distinctly uncommon, with only a handful of cases reported. We describe two children with CHARGE syndrome who presented with bilateral lower punctal agenesis and complex nasolacrimal duct obstruction (NLDO). The first patient had recurrent dacryocystitis and long-standing epiphora; examination revealed bilateral absence of the lower puncta, right NLDO, and partial stenosis of the left nasolacrimal duct. He underwent right external dacryocystorhinostomy and left lacrimal probing with bilateral monocanalicular stenting, resulting in resolution of infection and marked reduction of tearing. The second patient had bilateral bony obstruction; probing revealed a hard stop within the duct that prevented stent placement, and surgery was deferred. These cases expand the limited spectrum of lacrimal anomalies in CHARGE syndrome and highlight the importance of careful lacrimal evaluation and the potential role of CT imaging in guiding management.
2026-01-20 | Cochlear Implantation Via Extended Endaural Incision in a Patient With Congenital Ear Malformation.
In our previous report, we described a surgical technique for cochlear implantation in canal wall down (CWD) ears. Specifically, this involved extending the endaural incision superiorly, harvesting a large temporal fascia flap, completely removing the tympanic epithelium, inserting the electrode array, obliterating the middle ear cavity with the temporal fascia flap, and sealing the external auditory canal with a tragal cartilage plug. This report details the safe application of this technique in a patient with severe ear malformation and suspected CHARGE syndrome, supplemented with a brief literature review. The patient was a 28-year-old woman with malformations of the auricle, middle ear, and inner ear, as well as patent ductus arteriosus, amblyopia, and mild intellectual disability.Temporal bone CT revealed significant inferior displacement of the emissary vein, precluding standard electrode insertion via the posterior tympanotomy approach to the round window. We therefore applied our previously reported technique to this malformed ear without prior surgical history. Sequential bilateral implantation was performed. Surgical duration was 96 minutes (right) and 167 minutes (left). Wide bony exposure via CWD facilitated uneventful electrode insertion bilaterally, with minimal bleeding. Postoperative sound-field aided thresholds were favorable at 35 dB (right) and 38.3 dB (left). Speech discrimination scores were 90% at 60 dB (right) and 0% (left). The cochlear implantation technique for CWD ears was safely adapted to this patient with congenital malformation. This approach represents a viable surgical option for cases with severe malformations such as CHARGE syndrome.
proteins
2026-09-22 | A CHD7 intronic variant induces aberrant splicing and structural alterations in the CHD7 DNA-binding domain to cause CHARGE syndrome.
CHARGE syndrome (CS), a rare inherited condition, is mainly caused by pathogenic variants in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). In the present investigation, the genetic etiology of CS was elucidated in a Chinese patient presenting with characteristic clinical features. A 28-year-old female with amenorrhea, facial asymmetry, right ear malformation, hearing impairment, and congenital cardiac anomalies was evaluated using whole-exome sequencing (WES) for mutation screening. Familial Sanger sequencing subsequently confirmed the identified variant as de novo. Minigene assays were used to assess the pathogenicity of the splicing variant, while the structural alterations in CHD7 were characterized using computational modeling and electrostatic potential analyses. WES detected a heterozygous CHD7 splice-site variant, c.5405-17 G>A, which was not detected in either parent. Minigene-based functional assessments revealed this de novo CHD7 variant to cause a 15-bp insertion, resulting in a five-amino-acid insertion between the helicase and the SANT domains of CHD7, thereby potentially altering DNA binding. Hormone replacement therapy successfully induced cyclic menstruation, and surgical intervention corrected the auricular deformity. A de novo pathogenic splice-site mutation (c.5405-17 G>A) was identified in this study, which leads to the pathogenesis of CS. Subsequent functional evaluation confirmed that this mutation disrupts normal mRNA processing, thereby inducing structural alterations in the CHD7 protein. The results obtained herein advance our understanding of the mutational spectrum of CHD7, while emphasizing the importance of combining clinical, genetic, and functional analyses for the definitive diagnosis of CS.
2026-05-01 | Immunological Aspects of CHARGE Syndrome on the Example of Four Clinical Case Reports
Background and Aims CHARGE syndrome (OMIM#214800) is a rare hereditary monogenic disease with an autosomal-dominant pattern of inheritance. It is characterized by multiple congenital malformations and is caused by pathogenic variants in the CHD7 gene. Immunological disorders are typically associated with thymic hypoplasia or aplasia and vary in their clinical manifestations. The diagnosis of immunological disorders in patients with CHARGE syndrome requires a comprehensive assessment that includes the analysis of immunoglobulin levels, the evaluation of T and B lymphocyte function, and the assessment of the response to vaccination. Early detection and appropriate treatment of immunodeficiencies in children with CHARGE syndrome are crucial for preventing severe infections and improving the prognosis. Methods The patients’ phenotype was assessed based on the results of a clinical examination and instrumental and laboratory tests. The children’s physical development was evaluated using the World Health Organization program Anthro. A cytogenetic study was conducted on lymphocytes using standard protocols (G-banding). A molecular genetic study was performed on the probands using full exome sequencing, and the segregation of the identified variants in the families was determined using Sanger sequencing. The functioning of the T and B cell immune system was assessed by determining the quantitative analysis of T cell receptor excision circles (TREC)/kappa-deleting recombination excision circles (KREC) using real-time quantitative (RQ) PCR. Results 4 patients from 4 families were diagnosed with CHARGE syndrome based on clinical data and genetically verified variants in the CHD7 gene. The family histories of these families were not affected. All patients had a normal karyotype. An immunological study showed that the absolute number of lymphocytes was low (1,050[1,010;1,400] cells/ml). Examination of blood samples from neonatal screening forms revealed a decrease in the TREC (0.0[0; 300] copies x10 6 leukocytes) at normal KREC 3,420[3,050–4,980] copies x10 6 leukocytes). Conclusions The results we obtained demonstrate the clinical significance of the TREC/KREC study within the framework of neonatal screening, not only in relation to the diagnosis of primary immunodeficiencies but also for syndromic diseases accompanied by immune system insufficiency. These data can serve as a basis for in-depth immunological examination of patients, timely initiation of preventive measures to prevent infectious diseases, and timely prescription of replacement therapy.
2025-11-10 | CHD7 regulates cardiac neural crest cell differentiation through SOX5-mediated self-activation.
CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and development, genital abnormalities, and ear anomalies) syndrome, primarily caused by CHD7 haploinsufficiency, is a complex developmental disorder frequently associated with congenital heart defects. Our comprehensive single-cell RNA sequencing (scRNA-seq) analysis of cardiac neural crest cells (cNCCs) with Chd7 inactivation reveals impaired myocyte differentiation by cNCCs as a major cellular defect; loss of Chd7 disrupts myogenic transcriptional programs, alters cell fate trajectories, and activates cellular stress responses. These results significantly advance our understanding of the NCC-autonomous role of CHD7 and the mechanisms underlying CHARGE-associated heart defects driven by cNCC dysfunction. We further discovered that CHD7 enhances its own expression through interaction with SOX5 at an upstream enhancer conserved among mammals. Notably, SOX5 overexpression in cultured Chd7-haploinsufficient cNCCs restores Chd7 expression from the intact allele and rescues myocyte differentiation. These findings uncover a SOX5-mediated Chd7 autoregulatory mechanism and suggest that enhancing the SOX5-CHD7 axis may represent a promising strategy to mitigate cardiovascular defects caused by CHD7 insufficiency.
2022-01-13 | A case of migraine treatment in a patient with a clinical diagnosis of CHARGE syndrome using onabotulinum toxin A.
CHARGE syndrome is a genetic disorder that affects multiple organ and sensory systems. Cranial nerve involvement is one of the key clinical diagnostic criteria. We present the case of an 8-year-old girl with CHARGE syndrome, associated right-sided facial palsy, and chronic severe migraines, that were intractable to medical treatment. At age 6, onabotulinum toxin A was used to weaken the contralateral non-paralyzed side of her face to address her stigmatizing asymmetry. Onabotulinum toxin A chemodenervation was performed on the left lower lip depressors to relax the muscles and improve left lower lip position. Coincidentally, it was noted that with these treatments, migraine symptoms resolved. As the chemodenervation subsided over the next 3-4 months, the severe migraines returned. Continued treatment with onabotulinum toxin A injections every 3 months has resulted in ongoing improvements in facial symmetry and migraine control. Onabotulinum toxin A is a well-known treatment of chronic migraine. Injections are usually directed to the occipitalis, frontalis, and corrugator muscles. The literature has no reports of injections to the lower lip depressors as a useful therapy for migraine, making the results from this case unique.
2020-03-30 | Neonatal presentation of growth hormone deficiency in CHARGE syndrome: the benefit of early treatment on long-term growth
CHARGE syndrome is a complex disorder involving multiple congenital anomalies and is caused by heterozygous mutations in the CHD7 gene.Growth retardation is a characteristic finding and about 10% of cases present growth hormone (GH) deficiency.GH treatment of short stature in CHARGE syndrome has shown some benefit, but normal height is rarely attained.We report a girl with CHARGE syndrome due to a de novo frameshift mutation in the CHD7 gene (c.2509_2512delCATT), in whom recurrent hypoglycaemia led to the diagnosis of GH deficiency in the second month of life.Early initiation of treatment with recombinant GH resulted in normal growth over ten years of follow-up.This case is the youngest reported CHARGE patient to be diagnosed and treated for GH deficiency and demonstrates that GH deficiency in CHARGE syndrome may manifest early in life through hypoglycaemia, before growth retardation is noted, and can be successfully treated with recombinant GH.
small molecules
2026-09-17 | Endoscopic recannulation with temporary steroid-eluting biodegradable stenting as a bridge strategy for complete subglottic stenosis in a child with CHARGE syndrome.
Complete (Cotton-Myer grade IV) subglottic stenosis (SGS) is a severe form of airway obstruction traditionally managed with open airway reconstruction. Children with CHARGE syndrome frequently present with complex airway abnormalities and medical comorbidities that may complicate airway management and increase surgical risk.We report the case of a toddler with CHARGE syndrome who developed complete SGS following prolonged neonatal intubation and multiple failed extubation attempts. Given the patient's complex medical condition and high risk for open airway reconstruction, an endoscopic approach was pursued at 21 months of age. The stenotic segment was recannulated using a needle-guided technique followed by cold steel incision and balloon dilation. A temporary mini-PROPEL steroid-eluting biodegradable stent was placed adjunctively across the recannulated segment.Follow-up endoscopy demonstrated maintenance of airway patency without significant granulation tissue. The patient subsequently underwent successful single-stage laryngotracheal reconstruction and remained tracheostomy-free.This case demonstrates that complete subglottic obstruction may be amenable to endoscopic recannulation. In medically fragile children, temporary biodegradable steroid-eluting stenting may serve as a minimally invasive bridge to definitive airway reconstruction.
2026-06-23 | ID #18 CHD7-associated CHARGE Syndrome and a spinal schwannoma with a SH3PXD2A::HTRA1 fusion: A case report
Abstract Background CHARGE syndrome is a genetic malformation disorder with a wide range of phenotypes. Most commonly, the syndrome is characterized by colobomas, heart disease, choanal atresia, growth delay, intellectual disabilities, genital anomalies, and ear malformations.[1] It is associated with CHD7 gene mutations.[2]The CHD7 gene is part of the chromodomain helicase deoxyribonucleic acid-binding protein family and helps to regulate chromatin organization, which is key for the development of organ systems.[2] Alterations of the CHD7 gene are not classified as a cancer predisposition syndrome, though changes in the gene are reported to be oncogenic.[3] Despite this, CHARGE syndrome is not commonly associated with tumors or malignancies. Schwannomas are benign peripheral nerve sheath tumors, which have genetic drivers outside of associations with NF2-related schwannomatosis, including CHD7::VGLL3 and SH3PXD2A::HTRA1 fusions.[4-6] Case We are reporting on a case of a 19-year-old male with CHARGE syndrome who developed a spinal schwannoma. His presentation was characterized by worsening pain and weakness over 6 months. An MRI identified a 3cm3 mass at the level of thoracic spine vertebrae T10 and T11, which was resected. A SH3PXD2A::HTRA1 fusion was identified, which is a novel finding in the setting of CHD7-mutated CHARGE syndrome. Post-operative surveillance imaging has been stable for 4 years. Conclusion VGLL3 is a common rearrangement in hybrid schwannoma-perineuriomas, including fusions of CHD7::VGLL3.[7] The SH3PXD2A::HTRA1 fusion, which acts to promote tumorigenesis and cell proliferation likely via the MEK-ERK pathway, is a relatively recent finding.[5,8] In some preclinical studies, the growth of fusion-positive cells was suppressed by a MEK inhibitor.[5] The hope is that ultimately, the fusion could serve as a therapeutic target. Further research is important to better understand the identified SH3PXD2A::HTRA1 fusion and its implications for schwannomas and CHARGE syndrome, specifically the possible need for routine cancer surveillance and the possibility of targeted treatments. 1. Usman N, Sur M. CHARGE Syndrome. StatPearls. 2025; 2. Sanlaville D, Verloes A. CHARGE syndrome: an update. European Journal of Human Genetics. 2007/04/01 2007;15(4):389-399. doi:10.1038/sj.ejhg.5201778 3. Shuto M, Hirano N, Oguri S, et al. Acute myeloid leukemia associated with CHARGE syndrome. American Journal of Medical Genetics Part A. 2023;191(3):878-881. doi:https://doi.org/10.1002/ajmg.a.63087 4. Flucke UE, Hiemcke-Jiwa LS, Wesseling P. Unraveling schwannomas. Neuro Oncol. Dec 8 2023;25(12):2237-2238. doi:10.1093/neuonc/noad171 5. Agnihotri S, Jalali S, Wilson MR, et al. The genomic landscape of schwannoma. Nature Genetics. 2016/11/01 2016;48(11):1339-1348. doi:10.1038/ng.3688 6. Special Issue: Abstracts of the 20th International Congress of Neuropathology, Berlin, Germany, September 13–16, 2023. Brain Pathology. 2023;33(S1):e13194. doi:https://doi.org/10.1111/bpa.13194 7. Dickson BC, Antonescu CR, Demicco EG, et al. Hybrid schwannoma-perineurioma frequently harbors VGLL3 rearrangement. Mod Pathol. Jun 2021;34(6):1116-1124. doi:10.1038/s41379-021-00783-0 8. Lee J-C, Lee P-H, Li S-C, et al. Systematic Characterization of the Clinical and Pathological Features of Schwannomas Harboring SH3PXD2A::HTRA1 Fusion. Modern Pathology. 2024/03/01/ 2024;37(3):100427. doi:https://doi.org/10.1016/j.modpat.2024.100427
2026-04-09 | Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterisation of chromatinopathies.
BACKGROUND: Recent advances in sequencing technologies have enhanced patient diagnosis; however, causal pathogenic variants remain unidentified for a significant number of patients due to limited understanding of certain variants, regulatory sequences, or sequencing challenges, such as complex rearrangements. Investigating the epigenetic landscape has become essential to improve the diagnostic yield. Diseases caused by pathogenic variants in epigenetic regulators, often associated with growth abnormalities, intellectual disability, and facial dysmorphism, are prime models for studying episignatures. Among them, Snijders Blok-Campeau syndrome (ORPHA:599082), caused by pathogenic variants in the CHD3 gene, remains largely understudied. METHODS: A European cohort of 23 patients displaying typical Snijders Blok-Campeau syndrome traits and carrying pathogenic/likely pathogenic CHD3 variants was analysed using the Illumina EPIC array, identifying 270 differentially methylated positions distinguishing patients from 62 healthy matched controls. A subset of these regions serves as diagnostic tools for complex cases or variants of uncertain significance and helps uncover deregulated pathways linked to this syndrome. Four patients carrying pathogenic/likely pathogenic variants but with atypical clinical presentation, as well as 10 patients with variants of uncertain significance, were analysed as the testing set. RESULTS: Comparing methylomes of patients carrying pathogenic variants in CHD3, CHD7 (CHARGE syndrome, ORPHA:138), and CHD8 (Intellectual developmental disorder with autism and macrocephaly, ORPHA:642675) genes allows us to identify distinct subgroups with unique methylation profiles. This CHD3 DNA methylation signature aids in reclassifying variants and diagnosing atypical cases. CONCLUSIONS: Our findings advance the field of epigenetic signatures in rare diseases. We have opened new avenues for further investigation into subtypes defined by methylome assays (such as in the context of chromatinopathies), which could refine the phenotype spectrum and help predict patient outcomes.
2026-04-02 | Integrated CHARGE syndrome models reveal epigenetic modulators of reproductive phenotypes
Abstract Loss-of-function variants in CHD7 cause CHARGE syndrome (CS), a rare developmental disorder showing multisystem malformations, including reproductive defects linked to gonadotropin-releasing hormone (GnRH) neuron dysfunction. CHD7 encodes a chromatin remodeler essential for early transcriptional regulation across various tissues. Currently, no pharmacological treatments exist, and approaches aimed at identifying tissue-specific CHD7 targets are also lacking, making CS treatment an unmet clinical need. To explore mechanisms relevant to CS-associated reproductive defects, we established a dual screening platform combining CRISPR-engineered Chd7 -depleted mouse GnRH neurons with a Caenorhabditis elegans chd-7 mutant showing reproductive abnormalities. Transcriptomic and functional analyses of Chd7 -deficient cells revealed impaired cellular processes along with dysregulation of semaphorin ( Sema ) genes, key regulators of GnRH neuron development. A screen of 234 epigenetic modulators in C. elegans identified compounds modifying aberrant mutant phenotype, two of which also rescued cellular defects and Sema expression in vitro. Altogether, these findings indicate that CHD7 deficiency reshapes neuroendocrine-relevant pathways and that selected compounds modulate CS-associated phenotypes across species, with SEMA signalling emerging as candidate druggable downstream pathway in CS requiring further mechanistic validation.
2026-02-26 | Congenital hyperinsulinism in an individual with CHARGE syndrome and a pathogenic CHD7 variant.
Hyperinsulinemic hypoglycemia (HI) is a rare feature in individuals with coloboma, heart defects, atresia choanae, retardation of growth and development, genital abnormalities, and ear abnormalities (CHARGE) syndrome, though its underlying mechanisms remain poorly understood. We report a Chilean female proband with genetically confirmed CHARGE syndrome caused by a pathogenic variant in the CHD7 gene, who presented with HI in the neonatal period. Initial hypoglycemia was detected on days 2-3 of life, followed by recurrent episodes prompting biochemical investigation. On day 21, HI was biochemically confirmed. Comprehensive hormonal evaluation, including cortisol and growth hormone testing, excluded deficiencies in these hormones as contributing factors. Genetic screening of 22 known HI-associated genes revealed no pathogenic variants, supporting the hypothesis that HI in this case is related to CHARGE syndrome rather than being a coincidental finding. The patient responded well to diazoxide treatment, which allowed for maintenance of normoglycemia, with gradual dose reduction as glucose management normalized. This case, along with 2 previously reported cases, suggests that HI can be an integral part of CHARGE syndrome. Further research is needed to understand the mechanisms connecting CHD7 variants and HI and to refine management strategies for affected individuals.
oligonucleotides
2023-09-06 | CHARGE syndrome-associated CHD7 acts at ISL1-regulated enhancers to modulate second heart field gene expression.
Haploinsufficiency of the chromo-domain protein CHD7 underlies most cases of CHARGE syndrome, a multisystem birth defect including congenital heart malformation. Context specific roles for CHD7 in various stem, progenitor, and differentiated cell lineages have been reported. Previously, we showed severe defects when Chd7 is absent from cardiopharyngeal mesoderm (CPM). Here, we investigate altered gene expression in the CPM and identify specific CHD7-bound target genes with known roles in the morphogenesis of affected structures. We generated conditional KO of Chd7 in CPM and analysed cardiac progenitor cells using transcriptomic and epigenomic analyses, in vivo expression analysis, and bioinformatic comparisons with existing datasets. We show CHD7 is required for correct expression of several genes established as major players in cardiac development, especially within the second heart field (SHF). We identified CHD7 binding sites in cardiac progenitor cells and found strong association with histone marks suggestive of dynamically regulated enhancers during the mesodermal to cardiac progenitor transition of mESC differentiation. Moreover, CHD7 shares a subset of its target sites with ISL1, a pioneer transcription factor in the cardiogenic gene regulatory network, including one enhancer modulating Fgf10 expression in SHF progenitor cells vs. differentiating cardiomyocytes. We show that CHD7 interacts with ISL1, binds ISL1-regulated cardiac enhancers, and modulates gene expression across the mesodermal heart fields during cardiac morphogenesis.
2023-05-25 | Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report
Abstract Background Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 ( CHD7 ) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome. Case presentation A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome. Conclusions We report a rare case of CPHD harboring CHD7 mutation without CHARGE syndrome. This case provides valuable insights into phenotypes caused by CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of CHD7-associated syndrome.
2022-03-28 | HERVH-derived lncRNAs negatively regulate chromatin targeting and remodeling mediated by CHD7.
Chd7 encodes an ATP-dependent chromatin remodeler which has been shown to target specific genomic loci and alter local transcription potentially by remodeling chromatin structure. De novo mutations in CHD7 are the major cause of CHARGE syndrome which features multiple developmental defects. We examined whether nuclear RNAs might contribute to its targeting and function and identified a preferential interaction between CHD7 and lncRNAs derived from HERVH loci in pluripotent stem cells. Knockdown of HERVH family lncRNAs using LNAs or knockout of an individual copy of HERVH by CRISPR-Cas9 both resulted in increased binding of CHD7 and increased levels of H3K27ac at a subset of enhancers. Depletion of HERVH family RNAs led to the activation of multiple genes. CHD7 bound HERVH RNA with high affinity but low specificity and this interaction decreased the ability of CHD7 to bind and remodel nucleosomes. We present a model in which HERVH lncRNAs act as a decoy to modulate the dynamics of CHD7 binding to enhancers in pluripotent cells and the activation of numerous genes that might impact the differentiation process.
2021-03-29 | Molecular Insights Into the Causes of Human Thymic Hypoplasia With Animal Models.
22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.
2021-03-23 | let-7 miRNAs inhibit CHD7 expression and control auditory-sensory progenitor cell behavior in the developing inner ear.
The evolutionarily conserved lethal-7 (let-7) microRNAs (miRNAs) are well-known activators of proliferative quiescence and terminal differentiation. However, in the murine auditory organ, let-7g overexpression delays the differentiation of mechano-sensory hair cells (HCs). To address whether the role of let-7 in auditory-sensory differentiation is conserved among vertebrates, we manipulated let-7 levels within the chicken auditory organ: the basilar papilla. Using a let-7 sponge construct to sequester let-7 miRNAs, we found that endogenous let-7 miRNAs are essential for limiting the self-renewal of HC progenitor cells. Furthermore, let-7b overexpression experiments revealed that, similar to mice, higher than normal let-7 levels slow/delay HC differentiation. Finally, we identify CHD7, a chromatin remodeler, as a candidate for mediating the repressive function of let-7 in HC differentiation and inner ear morphogenesis. Our analysis uncovered an evolutionarily conserved let-7-5p-binding site within the chicken Chd7 gene and its human and murine homologs, and we show that let-7g overexpression in mice limits CHD7 expression in the developing inner ear, retina and brain. Haploinsufficiency of CHD7 in humans causes CHARGE syndrome and attenuation of let-7 function may be an effective method for treating CHD7 deficiency.
other
2026-09-09 | Developmental senescence misregulation in congenital disorders: CHARGE syndrome as a candidate model.
Developmental senescence has recently emerged as a physiological program that contributes to tissue remodeling, morphogenesis and growth regulation during vertebrate embryogenesis. While transient and non-pathological under normal conditions, this program requires strict spatial and temporal control. Here we argue that its misregulation represents a source of congenital defects. In particular, we suggest that the deficiency of the chromatin remodeler CHD7, the major genetic cause of CHARGE syndrome, may disrupt the spatiotemporal boundaries of developmental senescence. This hypothesis is supported by several lines of evidence in vertebrate models: first, CHD7 expression domains during development largely overlap with regions where physiological embryonic senescence has been described. Second, CHD7 reduction is associated with altered cell proliferation and misregulation of key senescence-related pathways including those driven by p53, p21 and TGFβ. Disruption of this regulatory balance may alter the timing of cellular growth arrest, clearance and tissue differentiation, providing a plausible mechanistic framework for the multisystemic anomalies observed in CHARGE syndrome.
2026-05-30 | Mouse models and translational research progress of hereditary vestibular dysfunction.
BackgroundHereditary vestibular dysfunctions (HVDs) are a group of diseases caused by genetic mutations, characterized by congenital or progressive vestibular dysfunction, often accompanied by hearing loss or other systemic damages. These diseases are divided into syndromic (e.g., Usher syndrome, CHARGE syndrome) and non-syndromic types, involving mutations in key genes such as MYO7A, COCH, SLC26A4, TMC1, etc. Although clinical phenotypes vary, the pathogenesis is complex, traditional diagnostic methods are limited, and effective treatments are lacking. Mouse models are important tools for studying hereditary vestibular dysfunction, providing critical platforms for understanding disease mechanisms, developing diagnostic biomarkers, and treatment strategies.MethodsThis review systematically searched English and Chinese literature in databases including PubMed, Web of Science, Embase, and CNKI from January 2000 to April 2026. The search strategy combined Medical Subject Headings (MeSH) terms and free-text keywords, including "hereditary vestibular dysfunction," "mouse models," "gene therapy," "CRISPR-Cas9," "Usher syndrome," "translational research," "biomarkers," "Meniere disease," and "International Mouse Phenotyping Consortium." Inclusion criteria were: (1) peer-reviewed articles on hereditary vestibular dysfunction mouse models; (2) studies reporting genetic mechanisms, pathophysiology, or therapeutic interventions; and (3) English or Chinese language publications. Exclusion criteria were: (1) non-peer-reviewed conference abstracts or preprints and (2) studies without clear genetic or phenotypic characterization. Two authors independently screened titles, abstracts, and full texts, with disagreements resolved by consensus. The review focuses on analyzing the applications of spontaneous mutation models, genetic engineering models, CRISPR technology-based models, and knockout models from the International Mouse Phenotype Consortium (IMPC) in disease mechanism research and treatment development.ResultsIn recent years, significant progress has been made in hereditary vestibular dysfunction mouse model research. Spontaneous mutation models like Myo6 and Cdh23 mutant mice have revealed the key role of cytoskeletal and cell junctions in vestibular function. Genetic engineering models have successfully simulated a variety of diseases, including Usher syndrome, ion channel defects, and vestibular development abnormalities, elucidating the molecular mechanisms of TMC1/2 mechanosensory channels, SLC26A4 ion transport, and vestibular system development genes. The application of CRISPR-Cas9 technology has greatly improved model construction efficiency and precision. These models have shown positive results in gene therapy, gene editing, and drug treatment research. AAV-mediated gene replacement therapy, CRISPR gene repair, and new drugs such as α1-antitrypsin have all achieved positive outcomes in mouse models. Biomarker studies based on multi-omics techniques have identified potential diagnostic markers such as Slc17a6 and BDNF.ConclusionMouse models play an irreplaceable role in the study of hereditary vestibular dysfunction, providing a solid foundation for elucidating disease mechanisms, improving diagnostic methods, and developing treatment strategies. Although clinical translation still faces challenges such as species differences, delivery efficiency, and treatment windows, with the continuous development of gene editing technology, nano-delivery systems, and multi-omics techniques, personalized diagnosis and treatment for hereditary vestibular dysfunction are expected to be realized, bringing new hope to patients.
2026-03-24 | Clinical and genetic basis of congenital gonadotropin deficiency.
What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). FGFR1, ANOS1, and PROKR2 were most frequently mutated in KS, while GNRHR, FGFR1, and KISS1R predominated in nCHH. Oligogenic inheritance was detected in 15% of CHH cases, with variants in FGFR1 being most commonly involved. Importantly, a substantial proportion (14%) of CHH patients without a molecular diagnosis carried rare variants predicted to be P or LP in genes typically associated with CPHD (e.g. ROBO1, BRAF, FAT2, and DCHS2). Conversely, several CHH-associated genes such as FGFR1 and FGF8, already implicated in CPHD, were also identified in patients with CPHD and syndromic GN deficiency, further supporting a shared genetic architecture between CHH and CPHD. N/A. Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B_201275 to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests.
2026-02-10 | Multi-omic analyses identify molecular targets of Chd7 that contribute to CHARGE syndrome model phenotypes.
CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo variants in chromodomain helicase DNA binding protein 7 (CHD7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE syndrome phenotypes. To address this problem, here, we used a previously characterized zebrafish model of CHARGE syndrome to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, we identified that CRISPR/Cas9-mediated knockdown of capgb, nefla or rdh5 phenocopies behavioral defects seen in chd7 mutants, functionally validating the roles of these genes. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.
2025-08-06 | Multi-omic analyses identify molecular targets of Chd7 that mediate CHARGE syndrome model phenotypes.
CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo mutations in CHD7 (chromodomain helicase DNA binding protein 7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE phenotypes. To address this problem, here we used a previously characterized zebrafish CHARGE model to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway, and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, to functionally validate the roles of these genes, CRISPR/Cas9-mediated knockdown of capgb, nefla, or rdh5 phenocopies behavioral defects seen in chd7 mutants. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.
cell therapies
2026-06-18 | Cochlear Implantation and Hearing Rehabilitation in CHARGE Syndrome: Expanding Clinical Knowledge and Outcomes.
Characterize patients with CHARGE syndrome (CS) undergoing cochlear implantation (CI) and evaluate factors influencing surgical approaches and outcomes. Retrospective study. Quaternary pediatric referral center. Fifty-five patients with CS aged ≤21 years who underwent CI. Demographic, audiologic, radiologic, operative, and postoperative data were reviewed. Outcomes included audiologic performance, device use, communication modality, and the presence of facial nerve stimulation (FNS). Surgical feasibility, anatomic characteristics, and auditory outcomes. Fifty-five patients underwent CI, representing 67 ears. The cohort was 62% male, and 91% had neurodevelopmental impairment. Complete electrode insertion was achieved in 81% of ears (54/67), partial insertion in 5% (3/67), and insertion data were unavailable in 15% (10/67). Perimodiolar electrodes were used in 57% of ears. Imaging demonstrated cochlear nerve aplasia or hypoplasia in 54% of implanted ears and cochlear aperture stenosis in 25%. At analysis, 49% of patients were active CI users, while 27% had discontinued use. Audiologic threshold improvement was observed in 47% of patients, and overall clinical benefit was identified in 64% based on combined audiologic and functional measures. Ipsilateral facial nerve stimulation occurred in 15% of implanted ears; among these, 60% remained active users, while 40% discontinued CI use due to FNS unresponsive to reprogramming. CI is feasible and can provide meaningful benefit in patients with CS despite complex anatomic and neurodevelopmental challenges. These findings support an individualized approach to CI candidacy and offer practical guidance for surgical planning and family counseling regarding expected outcomes.
2026-06-04 | CHARGE Syndrome with Athymia Diagnosed by Newborn Screening and Treated with Cord Blood Transplantation: A Case Report
Background CHARGE syndrome is caused by pathogenic variants in the CHD7 gene and is characterized by coloboma, congenital heart defects, choanal atresia, growth retardation/developmental delay, genital hypoplasia, and ear anomalies with hearing loss. CHARGE syndrome with athymia can present with complete absence of the thymus, leading to T cell deficiency and a clinical phenotype of severe combined immunodeficiency (SCID). Early therapeutic intervention is required after diagnosis. Thymic transplantation is the curative treatment; however, when access is limited, hematopoietic stem cell transplantation (HSCT) may be an alternative. In Japan, reports of cord blood transplantation for CHARGE syndrome with athymia are limited, and cases diagnosed and treated before infectious complications through newborn screening (NBS) are extremely rare. Case A male infant was born at 41 weeks’ gestation, weighing 3,632 g. Expanded NBS at day 6 revealed T cell receptor excision circle (TREC) 0 copies, reported on day 16. Positive-pressure management, cessation of breastfeeding, antifungal and anti-CMV prophylaxis, and immunoglobulin replacement were promptly initiated. Genetic testing identified a known frameshift variant in CHD7, and together with imaging findings of thymic aplasia, the patient was diagnosed with CHARGE syndrome with athymia. On day 30, he underwent aortic arch repair for coarctation of the aorta. On day 66, he received a 7/8 HLA allele–matched cord blood transplant without conditioning. T cells appeared in peripheral blood on day 14 post-transplant. At 1 month, he developed stage 2 skin graft versus host disease (GVHD), currently managed with adjustment of immunosuppressive therapy; no other transplant-related complications or infections have occurred. Conclusion Although long-term outcomes after HSCT require further follow-up, this case demonstrates that diagnosis of CHARGE syndrome with athymia by NBS prior to infectious complications enabled early appropriate supportive care and treatment planning, which likely contributed to a reduced risk of transplant-related mortality.
2026-05-06 | Cochlear Implantation in Patients With CHARGE Syndrome: A Systematic Review and Meta-Analysis.
Currently, there are limited large studies exploring cochlear implantation (CI) outcomes in patients with CHARGE syndrome. We aim to evaluate preoperative and postoperative speech and auditory outcomes in patients with CHARGE syndrome undergoing CI from a review of published single-center studies. PubMed, Scopus, and CINAHL. A total of 15 studies were included for analysis, encompassing 85 CHARGE patients with a total of 99 implanted ears. Extracted data included demographic information, study characteristics, and speech perception and auditory outcomes. Pooled analyses of scaled auditory outcome measures were performed using standardized mean differences (SMDs). Risk of bias was assessed using the Joanna Briggs Critical Appraisal Checklist to evaluate the quality and validity of included studies. This meta-analysis demonstrates significant global postoperative improvement in auditory outcomes for patients with CHARGE syndrome who underwent CI. Meta-analyzed data showed a significant increase in Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) scores following CI, with an estimated overall pre/post mean difference of 11.9 ( P = 0.036), and a significant increase in categories of auditory performance (CAP) scores following CI, with an estimated overall pre/post mean difference of 2.9 ( P = 0.004). Despite the complexity of inner ear malformations in this population, these findings contribute to the growing body of evidence supporting the use of CIs in CHARGE patients.
2026-02-17 | Lacrimal drainage system involvement in CHARGE syndrome: a two-case report.
CHARGE syndrome is a rare multisystem disorder, with ocular colobomas being the most frequent ophthalmic manifestation. Lacrimal drainage system anomalies are distinctly uncommon, with only a handful of cases reported. We describe two children with CHARGE syndrome who presented with bilateral lower punctal agenesis and complex nasolacrimal duct obstruction (NLDO). The first patient had recurrent dacryocystitis and long-standing epiphora; examination revealed bilateral absence of the lower puncta, right NLDO, and partial stenosis of the left nasolacrimal duct. He underwent right external dacryocystorhinostomy and left lacrimal probing with bilateral monocanalicular stenting, resulting in resolution of infection and marked reduction of tearing. The second patient had bilateral bony obstruction; probing revealed a hard stop within the duct that prevented stent placement, and surgery was deferred. These cases expand the limited spectrum of lacrimal anomalies in CHARGE syndrome and highlight the importance of careful lacrimal evaluation and the potential role of CT imaging in guiding management.
2026-01-20 | Cochlear Implantation Via Extended Endaural Incision in a Patient With Congenital Ear Malformation.
In our previous report, we described a surgical technique for cochlear implantation in canal wall down (CWD) ears. Specifically, this involved extending the endaural incision superiorly, harvesting a large temporal fascia flap, completely removing the tympanic epithelium, inserting the electrode array, obliterating the middle ear cavity with the temporal fascia flap, and sealing the external auditory canal with a tragal cartilage plug. This report details the safe application of this technique in a patient with severe ear malformation and suspected CHARGE syndrome, supplemented with a brief literature review. The patient was a 28-year-old woman with malformations of the auricle, middle ear, and inner ear, as well as patent ductus arteriosus, amblyopia, and mild intellectual disability.Temporal bone CT revealed significant inferior displacement of the emissary vein, precluding standard electrode insertion via the posterior tympanotomy approach to the round window. We therefore applied our previously reported technique to this malformed ear without prior surgical history. Sequential bilateral implantation was performed. Surgical duration was 96 minutes (right) and 167 minutes (left). Wide bony exposure via CWD facilitated uneventful electrode insertion bilaterally, with minimal bleeding. Postoperative sound-field aided thresholds were favorable at 35 dB (right) and 38.3 dB (left). Speech discrimination scores were 90% at 60 dB (right) and 0% (left). The cochlear implantation technique for CWD ears was safely adapted to this patient with congenital malformation. This approach represents a viable surgical option for cases with severe malformations such as CHARGE syndrome.
proteins
2026-09-22 | A CHD7 intronic variant induces aberrant splicing and structural alterations in the CHD7 DNA-binding domain to cause CHARGE syndrome.
CHARGE syndrome (CS), a rare inherited condition, is mainly caused by pathogenic variants in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). In the present investigation, the genetic etiology of CS was elucidated in a Chinese patient presenting with characteristic clinical features. A 28-year-old female with amenorrhea, facial asymmetry, right ear malformation, hearing impairment, and congenital cardiac anomalies was evaluated using whole-exome sequencing (WES) for mutation screening. Familial Sanger sequencing subsequently confirmed the identified variant as de novo. Minigene assays were used to assess the pathogenicity of the splicing variant, while the structural alterations in CHD7 were characterized using computational modeling and electrostatic potential analyses. WES detected a heterozygous CHD7 splice-site variant, c.5405-17 G>A, which was not detected in either parent. Minigene-based functional assessments revealed this de novo CHD7 variant to cause a 15-bp insertion, resulting in a five-amino-acid insertion between the helicase and the SANT domains of CHD7, thereby potentially altering DNA binding. Hormone replacement therapy successfully induced cyclic menstruation, and surgical intervention corrected the auricular deformity. A de novo pathogenic splice-site mutation (c.5405-17 G>A) was identified in this study, which leads to the pathogenesis of CS. Subsequent functional evaluation confirmed that this mutation disrupts normal mRNA processing, thereby inducing structural alterations in the CHD7 protein. The results obtained herein advance our understanding of the mutational spectrum of CHD7, while emphasizing the importance of combining clinical, genetic, and functional analyses for the definitive diagnosis of CS.
2026-05-01 | Immunological Aspects of CHARGE Syndrome on the Example of Four Clinical Case Reports
Background and Aims CHARGE syndrome (OMIM#214800) is a rare hereditary monogenic disease with an autosomal-dominant pattern of inheritance. It is characterized by multiple congenital malformations and is caused by pathogenic variants in the CHD7 gene. Immunological disorders are typically associated with thymic hypoplasia or aplasia and vary in their clinical manifestations. The diagnosis of immunological disorders in patients with CHARGE syndrome requires a comprehensive assessment that includes the analysis of immunoglobulin levels, the evaluation of T and B lymphocyte function, and the assessment of the response to vaccination. Early detection and appropriate treatment of immunodeficiencies in children with CHARGE syndrome are crucial for preventing severe infections and improving the prognosis. Methods The patients’ phenotype was assessed based on the results of a clinical examination and instrumental and laboratory tests. The children’s physical development was evaluated using the World Health Organization program Anthro. A cytogenetic study was conducted on lymphocytes using standard protocols (G-banding). A molecular genetic study was performed on the probands using full exome sequencing, and the segregation of the identified variants in the families was determined using Sanger sequencing. The functioning of the T and B cell immune system was assessed by determining the quantitative analysis of T cell receptor excision circles (TREC)/kappa-deleting recombination excision circles (KREC) using real-time quantitative (RQ) PCR. Results 4 patients from 4 families were diagnosed with CHARGE syndrome based on clinical data and genetically verified variants in the CHD7 gene. The family histories of these families were not affected. All patients had a normal karyotype. An immunological study showed that the absolute number of lymphocytes was low (1,050[1,010;1,400] cells/ml). Examination of blood samples from neonatal screening forms revealed a decrease in the TREC (0.0[0; 300] copies x10 6 leukocytes) at normal KREC 3,420[3,050–4,980] copies x10 6 leukocytes). Conclusions The results we obtained demonstrate the clinical significance of the TREC/KREC study within the framework of neonatal screening, not only in relation to the diagnosis of primary immunodeficiencies but also for syndromic diseases accompanied by immune system insufficiency. These data can serve as a basis for in-depth immunological examination of patients, timely initiation of preventive measures to prevent infectious diseases, and timely prescription of replacement therapy.
2025-11-10 | CHD7 regulates cardiac neural crest cell differentiation through SOX5-mediated self-activation.
CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and development, genital abnormalities, and ear anomalies) syndrome, primarily caused by CHD7 haploinsufficiency, is a complex developmental disorder frequently associated with congenital heart defects. Our comprehensive single-cell RNA sequencing (scRNA-seq) analysis of cardiac neural crest cells (cNCCs) with Chd7 inactivation reveals impaired myocyte differentiation by cNCCs as a major cellular defect; loss of Chd7 disrupts myogenic transcriptional programs, alters cell fate trajectories, and activates cellular stress responses. These results significantly advance our understanding of the NCC-autonomous role of CHD7 and the mechanisms underlying CHARGE-associated heart defects driven by cNCC dysfunction. We further discovered that CHD7 enhances its own expression through interaction with SOX5 at an upstream enhancer conserved among mammals. Notably, SOX5 overexpression in cultured Chd7-haploinsufficient cNCCs restores Chd7 expression from the intact allele and rescues myocyte differentiation. These findings uncover a SOX5-mediated Chd7 autoregulatory mechanism and suggest that enhancing the SOX5-CHD7 axis may represent a promising strategy to mitigate cardiovascular defects caused by CHD7 insufficiency.
2022-01-13 | A case of migraine treatment in a patient with a clinical diagnosis of CHARGE syndrome using onabotulinum toxin A.
CHARGE syndrome is a genetic disorder that affects multiple organ and sensory systems. Cranial nerve involvement is one of the key clinical diagnostic criteria. We present the case of an 8-year-old girl with CHARGE syndrome, associated right-sided facial palsy, and chronic severe migraines, that were intractable to medical treatment. At age 6, onabotulinum toxin A was used to weaken the contralateral non-paralyzed side of her face to address her stigmatizing asymmetry. Onabotulinum toxin A chemodenervation was performed on the left lower lip depressors to relax the muscles and improve left lower lip position. Coincidentally, it was noted that with these treatments, migraine symptoms resolved. As the chemodenervation subsided over the next 3-4 months, the severe migraines returned. Continued treatment with onabotulinum toxin A injections every 3 months has resulted in ongoing improvements in facial symmetry and migraine control. Onabotulinum toxin A is a well-known treatment of chronic migraine. Injections are usually directed to the occipitalis, frontalis, and corrugator muscles. The literature has no reports of injections to the lower lip depressors as a useful therapy for migraine, making the results from this case unique.
2020-03-30 | Neonatal presentation of growth hormone deficiency in CHARGE syndrome: the benefit of early treatment on long-term growth
CHARGE syndrome is a complex disorder involving multiple congenital anomalies and is caused by heterozygous mutations in the CHD7 gene.Growth retardation is a characteristic finding and about 10% of cases present growth hormone (GH) deficiency.GH treatment of short stature in CHARGE syndrome has shown some benefit, but normal height is rarely attained.We report a girl with CHARGE syndrome due to a de novo frameshift mutation in the CHD7 gene (c.2509_2512delCATT), in whom recurrent hypoglycaemia led to the diagnosis of GH deficiency in the second month of life.Early initiation of treatment with recombinant GH resulted in normal growth over ten years of follow-up.This case is the youngest reported CHARGE patient to be diagnosed and treated for GH deficiency and demonstrates that GH deficiency in CHARGE syndrome may manifest early in life through hypoglycaemia, before growth retardation is noted, and can be successfully treated with recombinant GH.
small molecules
2026-09-17 | Endoscopic recannulation with temporary steroid-eluting biodegradable stenting as a bridge strategy for complete subglottic stenosis in a child with CHARGE syndrome.
Complete (Cotton-Myer grade IV) subglottic stenosis (SGS) is a severe form of airway obstruction traditionally managed with open airway reconstruction. Children with CHARGE syndrome frequently present with complex airway abnormalities and medical comorbidities that may complicate airway management and increase surgical risk.We report the case of a toddler with CHARGE syndrome who developed complete SGS following prolonged neonatal intubation and multiple failed extubation attempts. Given the patient's complex medical condition and high risk for open airway reconstruction, an endoscopic approach was pursued at 21 months of age. The stenotic segment was recannulated using a needle-guided technique followed by cold steel incision and balloon dilation. A temporary mini-PROPEL steroid-eluting biodegradable stent was placed adjunctively across the recannulated segment.Follow-up endoscopy demonstrated maintenance of airway patency without significant granulation tissue. The patient subsequently underwent successful single-stage laryngotracheal reconstruction and remained tracheostomy-free.This case demonstrates that complete subglottic obstruction may be amenable to endoscopic recannulation. In medically fragile children, temporary biodegradable steroid-eluting stenting may serve as a minimally invasive bridge to definitive airway reconstruction.
2026-06-23 | ID #18 CHD7-associated CHARGE Syndrome and a spinal schwannoma with a SH3PXD2A::HTRA1 fusion: A case report
Abstract Background CHARGE syndrome is a genetic malformation disorder with a wide range of phenotypes. Most commonly, the syndrome is characterized by colobomas, heart disease, choanal atresia, growth delay, intellectual disabilities, genital anomalies, and ear malformations.[1] It is associated with CHD7 gene mutations.[2]The CHD7 gene is part of the chromodomain helicase deoxyribonucleic acid-binding protein family and helps to regulate chromatin organization, which is key for the development of organ systems.[2] Alterations of the CHD7 gene are not classified as a cancer predisposition syndrome, though changes in the gene are reported to be oncogenic.[3] Despite this, CHARGE syndrome is not commonly associated with tumors or malignancies. Schwannomas are benign peripheral nerve sheath tumors, which have genetic drivers outside of associations with NF2-related schwannomatosis, including CHD7::VGLL3 and SH3PXD2A::HTRA1 fusions.[4-6] Case We are reporting on a case of a 19-year-old male with CHARGE syndrome who developed a spinal schwannoma. His presentation was characterized by worsening pain and weakness over 6 months. An MRI identified a 3cm3 mass at the level of thoracic spine vertebrae T10 and T11, which was resected. A SH3PXD2A::HTRA1 fusion was identified, which is a novel finding in the setting of CHD7-mutated CHARGE syndrome. Post-operative surveillance imaging has been stable for 4 years. Conclusion VGLL3 is a common rearrangement in hybrid schwannoma-perineuriomas, including fusions of CHD7::VGLL3.[7] The SH3PXD2A::HTRA1 fusion, which acts to promote tumorigenesis and cell proliferation likely via the MEK-ERK pathway, is a relatively recent finding.[5,8] In some preclinical studies, the growth of fusion-positive cells was suppressed by a MEK inhibitor.[5] The hope is that ultimately, the fusion could serve as a therapeutic target. Further research is important to better understand the identified SH3PXD2A::HTRA1 fusion and its implications for schwannomas and CHARGE syndrome, specifically the possible need for routine cancer surveillance and the possibility of targeted treatments. 1. Usman N, Sur M. CHARGE Syndrome. StatPearls. 2025; 2. Sanlaville D, Verloes A. CHARGE syndrome: an update. European Journal of Human Genetics. 2007/04/01 2007;15(4):389-399. doi:10.1038/sj.ejhg.5201778 3. Shuto M, Hirano N, Oguri S, et al. Acute myeloid leukemia associated with CHARGE syndrome. American Journal of Medical Genetics Part A. 2023;191(3):878-881. doi:https://doi.org/10.1002/ajmg.a.63087 4. Flucke UE, Hiemcke-Jiwa LS, Wesseling P. Unraveling schwannomas. Neuro Oncol. Dec 8 2023;25(12):2237-2238. doi:10.1093/neuonc/noad171 5. Agnihotri S, Jalali S, Wilson MR, et al. The genomic landscape of schwannoma. Nature Genetics. 2016/11/01 2016;48(11):1339-1348. doi:10.1038/ng.3688 6. Special Issue: Abstracts of the 20th International Congress of Neuropathology, Berlin, Germany, September 13–16, 2023. Brain Pathology. 2023;33(S1):e13194. doi:https://doi.org/10.1111/bpa.13194 7. Dickson BC, Antonescu CR, Demicco EG, et al. Hybrid schwannoma-perineurioma frequently harbors VGLL3 rearrangement. Mod Pathol. Jun 2021;34(6):1116-1124. doi:10.1038/s41379-021-00783-0 8. Lee J-C, Lee P-H, Li S-C, et al. Systematic Characterization of the Clinical and Pathological Features of Schwannomas Harboring SH3PXD2A::HTRA1 Fusion. Modern Pathology. 2024/03/01/ 2024;37(3):100427. doi:https://doi.org/10.1016/j.modpat.2024.100427
2026-04-09 | Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterisation of chromatinopathies.
BACKGROUND: Recent advances in sequencing technologies have enhanced patient diagnosis; however, causal pathogenic variants remain unidentified for a significant number of patients due to limited understanding of certain variants, regulatory sequences, or sequencing challenges, such as complex rearrangements. Investigating the epigenetic landscape has become essential to improve the diagnostic yield. Diseases caused by pathogenic variants in epigenetic regulators, often associated with growth abnormalities, intellectual disability, and facial dysmorphism, are prime models for studying episignatures. Among them, Snijders Blok-Campeau syndrome (ORPHA:599082), caused by pathogenic variants in the CHD3 gene, remains largely understudied. METHODS: A European cohort of 23 patients displaying typical Snijders Blok-Campeau syndrome traits and carrying pathogenic/likely pathogenic CHD3 variants was analysed using the Illumina EPIC array, identifying 270 differentially methylated positions distinguishing patients from 62 healthy matched controls. A subset of these regions serves as diagnostic tools for complex cases or variants of uncertain significance and helps uncover deregulated pathways linked to this syndrome. Four patients carrying pathogenic/likely pathogenic variants but with atypical clinical presentation, as well as 10 patients with variants of uncertain significance, were analysed as the testing set. RESULTS: Comparing methylomes of patients carrying pathogenic variants in CHD3, CHD7 (CHARGE syndrome, ORPHA:138), and CHD8 (Intellectual developmental disorder with autism and macrocephaly, ORPHA:642675) genes allows us to identify distinct subgroups with unique methylation profiles. This CHD3 DNA methylation signature aids in reclassifying variants and diagnosing atypical cases. CONCLUSIONS: Our findings advance the field of epigenetic signatures in rare diseases. We have opened new avenues for further investigation into subtypes defined by methylome assays (such as in the context of chromatinopathies), which could refine the phenotype spectrum and help predict patient outcomes.
2026-04-02 | Integrated CHARGE syndrome models reveal epigenetic modulators of reproductive phenotypes
Abstract Loss-of-function variants in CHD7 cause CHARGE syndrome (CS), a rare developmental disorder showing multisystem malformations, including reproductive defects linked to gonadotropin-releasing hormone (GnRH) neuron dysfunction. CHD7 encodes a chromatin remodeler essential for early transcriptional regulation across various tissues. Currently, no pharmacological treatments exist, and approaches aimed at identifying tissue-specific CHD7 targets are also lacking, making CS treatment an unmet clinical need. To explore mechanisms relevant to CS-associated reproductive defects, we established a dual screening platform combining CRISPR-engineered Chd7 -depleted mouse GnRH neurons with a Caenorhabditis elegans chd-7 mutant showing reproductive abnormalities. Transcriptomic and functional analyses of Chd7 -deficient cells revealed impaired cellular processes along with dysregulation of semaphorin ( Sema ) genes, key regulators of GnRH neuron development. A screen of 234 epigenetic modulators in C. elegans identified compounds modifying aberrant mutant phenotype, two of which also rescued cellular defects and Sema expression in vitro. Altogether, these findings indicate that CHD7 deficiency reshapes neuroendocrine-relevant pathways and that selected compounds modulate CS-associated phenotypes across species, with SEMA signalling emerging as candidate druggable downstream pathway in CS requiring further mechanistic validation.
2026-02-26 | Congenital hyperinsulinism in an individual with CHARGE syndrome and a pathogenic CHD7 variant.
Hyperinsulinemic hypoglycemia (HI) is a rare feature in individuals with coloboma, heart defects, atresia choanae, retardation of growth and development, genital abnormalities, and ear abnormalities (CHARGE) syndrome, though its underlying mechanisms remain poorly understood. We report a Chilean female proband with genetically confirmed CHARGE syndrome caused by a pathogenic variant in the CHD7 gene, who presented with HI in the neonatal period. Initial hypoglycemia was detected on days 2-3 of life, followed by recurrent episodes prompting biochemical investigation. On day 21, HI was biochemically confirmed. Comprehensive hormonal evaluation, including cortisol and growth hormone testing, excluded deficiencies in these hormones as contributing factors. Genetic screening of 22 known HI-associated genes revealed no pathogenic variants, supporting the hypothesis that HI in this case is related to CHARGE syndrome rather than being a coincidental finding. The patient responded well to diazoxide treatment, which allowed for maintenance of normoglycemia, with gradual dose reduction as glucose management normalized. This case, along with 2 previously reported cases, suggests that HI can be an integral part of CHARGE syndrome. Further research is needed to understand the mechanisms connecting CHD7 variants and HI and to refine management strategies for affected individuals.
oligonucleotides
2023-09-06 | CHARGE syndrome-associated CHD7 acts at ISL1-regulated enhancers to modulate second heart field gene expression.
Haploinsufficiency of the chromo-domain protein CHD7 underlies most cases of CHARGE syndrome, a multisystem birth defect including congenital heart malformation. Context specific roles for CHD7 in various stem, progenitor, and differentiated cell lineages have been reported. Previously, we showed severe defects when Chd7 is absent from cardiopharyngeal mesoderm (CPM). Here, we investigate altered gene expression in the CPM and identify specific CHD7-bound target genes with known roles in the morphogenesis of affected structures. We generated conditional KO of Chd7 in CPM and analysed cardiac progenitor cells using transcriptomic and epigenomic analyses, in vivo expression analysis, and bioinformatic comparisons with existing datasets. We show CHD7 is required for correct expression of several genes established as major players in cardiac development, especially within the second heart field (SHF). We identified CHD7 binding sites in cardiac progenitor cells and found strong association with histone marks suggestive of dynamically regulated enhancers during the mesodermal to cardiac progenitor transition of mESC differentiation. Moreover, CHD7 shares a subset of its target sites with ISL1, a pioneer transcription factor in the cardiogenic gene regulatory network, including one enhancer modulating Fgf10 expression in SHF progenitor cells vs. differentiating cardiomyocytes. We show that CHD7 interacts with ISL1, binds ISL1-regulated cardiac enhancers, and modulates gene expression across the mesodermal heart fields during cardiac morphogenesis.
2023-05-25 | Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report
Abstract Background Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 ( CHD7 ) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome. Case presentation A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome. Conclusions We report a rare case of CPHD harboring CHD7 mutation without CHARGE syndrome. This case provides valuable insights into phenotypes caused by CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of CHD7-associated syndrome.
2022-03-28 | HERVH-derived lncRNAs negatively regulate chromatin targeting and remodeling mediated by CHD7.
Chd7 encodes an ATP-dependent chromatin remodeler which has been shown to target specific genomic loci and alter local transcription potentially by remodeling chromatin structure. De novo mutations in CHD7 are the major cause of CHARGE syndrome which features multiple developmental defects. We examined whether nuclear RNAs might contribute to its targeting and function and identified a preferential interaction between CHD7 and lncRNAs derived from HERVH loci in pluripotent stem cells. Knockdown of HERVH family lncRNAs using LNAs or knockout of an individual copy of HERVH by CRISPR-Cas9 both resulted in increased binding of CHD7 and increased levels of H3K27ac at a subset of enhancers. Depletion of HERVH family RNAs led to the activation of multiple genes. CHD7 bound HERVH RNA with high affinity but low specificity and this interaction decreased the ability of CHD7 to bind and remodel nucleosomes. We present a model in which HERVH lncRNAs act as a decoy to modulate the dynamics of CHD7 binding to enhancers in pluripotent cells and the activation of numerous genes that might impact the differentiation process.
2021-03-29 | Molecular Insights Into the Causes of Human Thymic Hypoplasia With Animal Models.
22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.
2021-03-23 | let-7 miRNAs inhibit CHD7 expression and control auditory-sensory progenitor cell behavior in the developing inner ear.
The evolutionarily conserved lethal-7 (let-7) microRNAs (miRNAs) are well-known activators of proliferative quiescence and terminal differentiation. However, in the murine auditory organ, let-7g overexpression delays the differentiation of mechano-sensory hair cells (HCs). To address whether the role of let-7 in auditory-sensory differentiation is conserved among vertebrates, we manipulated let-7 levels within the chicken auditory organ: the basilar papilla. Using a let-7 sponge construct to sequester let-7 miRNAs, we found that endogenous let-7 miRNAs are essential for limiting the self-renewal of HC progenitor cells. Furthermore, let-7b overexpression experiments revealed that, similar to mice, higher than normal let-7 levels slow/delay HC differentiation. Finally, we identify CHD7, a chromatin remodeler, as a candidate for mediating the repressive function of let-7 in HC differentiation and inner ear morphogenesis. Our analysis uncovered an evolutionarily conserved let-7-5p-binding site within the chicken Chd7 gene and its human and murine homologs, and we show that let-7g overexpression in mice limits CHD7 expression in the developing inner ear, retina and brain. Haploinsufficiency of CHD7 in humans causes CHARGE syndrome and attenuation of let-7 function may be an effective method for treating CHD7 deficiency.
other
2026-09-09 | Developmental senescence misregulation in congenital disorders: CHARGE syndrome as a candidate model.
Developmental senescence has recently emerged as a physiological program that contributes to tissue remodeling, morphogenesis and growth regulation during vertebrate embryogenesis. While transient and non-pathological under normal conditions, this program requires strict spatial and temporal control. Here we argue that its misregulation represents a source of congenital defects. In particular, we suggest that the deficiency of the chromatin remodeler CHD7, the major genetic cause of CHARGE syndrome, may disrupt the spatiotemporal boundaries of developmental senescence. This hypothesis is supported by several lines of evidence in vertebrate models: first, CHD7 expression domains during development largely overlap with regions where physiological embryonic senescence has been described. Second, CHD7 reduction is associated with altered cell proliferation and misregulation of key senescence-related pathways including those driven by p53, p21 and TGFβ. Disruption of this regulatory balance may alter the timing of cellular growth arrest, clearance and tissue differentiation, providing a plausible mechanistic framework for the multisystemic anomalies observed in CHARGE syndrome.
2026-05-30 | Mouse models and translational research progress of hereditary vestibular dysfunction.
BackgroundHereditary vestibular dysfunctions (HVDs) are a group of diseases caused by genetic mutations, characterized by congenital or progressive vestibular dysfunction, often accompanied by hearing loss or other systemic damages. These diseases are divided into syndromic (e.g., Usher syndrome, CHARGE syndrome) and non-syndromic types, involving mutations in key genes such as MYO7A, COCH, SLC26A4, TMC1, etc. Although clinical phenotypes vary, the pathogenesis is complex, traditional diagnostic methods are limited, and effective treatments are lacking. Mouse models are important tools for studying hereditary vestibular dysfunction, providing critical platforms for understanding disease mechanisms, developing diagnostic biomarkers, and treatment strategies.MethodsThis review systematically searched English and Chinese literature in databases including PubMed, Web of Science, Embase, and CNKI from January 2000 to April 2026. The search strategy combined Medical Subject Headings (MeSH) terms and free-text keywords, including "hereditary vestibular dysfunction," "mouse models," "gene therapy," "CRISPR-Cas9," "Usher syndrome," "translational research," "biomarkers," "Meniere disease," and "International Mouse Phenotyping Consortium." Inclusion criteria were: (1) peer-reviewed articles on hereditary vestibular dysfunction mouse models; (2) studies reporting genetic mechanisms, pathophysiology, or therapeutic interventions; and (3) English or Chinese language publications. Exclusion criteria were: (1) non-peer-reviewed conference abstracts or preprints and (2) studies without clear genetic or phenotypic characterization. Two authors independently screened titles, abstracts, and full texts, with disagreements resolved by consensus. The review focuses on analyzing the applications of spontaneous mutation models, genetic engineering models, CRISPR technology-based models, and knockout models from the International Mouse Phenotype Consortium (IMPC) in disease mechanism research and treatment development.ResultsIn recent years, significant progress has been made in hereditary vestibular dysfunction mouse model research. Spontaneous mutation models like Myo6 and Cdh23 mutant mice have revealed the key role of cytoskeletal and cell junctions in vestibular function. Genetic engineering models have successfully simulated a variety of diseases, including Usher syndrome, ion channel defects, and vestibular development abnormalities, elucidating the molecular mechanisms of TMC1/2 mechanosensory channels, SLC26A4 ion transport, and vestibular system development genes. The application of CRISPR-Cas9 technology has greatly improved model construction efficiency and precision. These models have shown positive results in gene therapy, gene editing, and drug treatment research. AAV-mediated gene replacement therapy, CRISPR gene repair, and new drugs such as α1-antitrypsin have all achieved positive outcomes in mouse models. Biomarker studies based on multi-omics techniques have identified potential diagnostic markers such as Slc17a6 and BDNF.ConclusionMouse models play an irreplaceable role in the study of hereditary vestibular dysfunction, providing a solid foundation for elucidating disease mechanisms, improving diagnostic methods, and developing treatment strategies. Although clinical translation still faces challenges such as species differences, delivery efficiency, and treatment windows, with the continuous development of gene editing technology, nano-delivery systems, and multi-omics techniques, personalized diagnosis and treatment for hereditary vestibular dysfunction are expected to be realized, bringing new hope to patients.
2026-03-24 | Clinical and genetic basis of congenital gonadotropin deficiency.
What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). FGFR1, ANOS1, and PROKR2 were most frequently mutated in KS, while GNRHR, FGFR1, and KISS1R predominated in nCHH. Oligogenic inheritance was detected in 15% of CHH cases, with variants in FGFR1 being most commonly involved. Importantly, a substantial proportion (14%) of CHH patients without a molecular diagnosis carried rare variants predicted to be P or LP in genes typically associated with CPHD (e.g. ROBO1, BRAF, FAT2, and DCHS2). Conversely, several CHH-associated genes such as FGFR1 and FGF8, already implicated in CPHD, were also identified in patients with CPHD and syndromic GN deficiency, further supporting a shared genetic architecture between CHH and CPHD. N/A. Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B_201275 to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests.
2026-02-10 | Multi-omic analyses identify molecular targets of Chd7 that contribute to CHARGE syndrome model phenotypes.
CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo variants in chromodomain helicase DNA binding protein 7 (CHD7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE syndrome phenotypes. To address this problem, here, we used a previously characterized zebrafish model of CHARGE syndrome to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, we identified that CRISPR/Cas9-mediated knockdown of capgb, nefla or rdh5 phenocopies behavioral defects seen in chd7 mutants, functionally validating the roles of these genes. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.
2025-08-06 | Multi-omic analyses identify molecular targets of Chd7 that mediate CHARGE syndrome model phenotypes.
CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo mutations in CHD7 (chromodomain helicase DNA binding protein 7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE phenotypes. To address this problem, here we used a previously characterized zebrafish CHARGE model to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway, and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, to functionally validate the roles of these genes, CRISPR/Cas9-mediated knockdown of capgb, nefla, or rdh5 phenocopies behavioral defects seen in chd7 mutants. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.
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Drug Discovery Landscape
1 orphan drug designation for CHARGE syndrome.
1 orphan drug designation for CHARGE syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Allogeneic cultured postnatal thymus-derived tissue | cell therapies | EMA | — | Myovant Sciences Ireland Limited |
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