RARE DISEASE
Smith-Magenis syndrome
Smith-Magenis syndrome
Smith-Magenis syndrome
Synonyms: 17p11.2 microdeletion syndrome
Synonyms: 17p11.2 microdeletion syndrome
Synonyms: 17p11.2 microdeletion syndrome
Drug discovery
6
drugs
With orphan designations
Overview
Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a heterozygous 17p11.2 deletion (90%) or RAI1 mutation (10%), characterized by intellectual disability, sleep-wake inversion (due to disrupted circadian melatonin secretion), distinctive craniofacial features, and behavioral challenges (self-injury, hyperactivity). Common comorbidities include speech delays, scoliosis, recurrent infections, and obesity [1][2][5][13][17]. Management focuses on melatonin regulation, behavioral interventions, and multidisciplinary support [3][8][12].
Burden
High caregiver strain due to chronic sleep disruption, behavioral crises, and frequent medical needs (e.g., infections, surgeries) [9][13][19].
Lifelong disability with 70–96% requiring speech/OT support; 25–45% have congenital heart/renal defects [5][15][17].
Increased hospitalization risks from self-injury, respiratory infections, and seizure comorbidities [9][15][19].
Therapies
Sleep: Nighttime melatonin supplementation + morning β1-blockers (e.g., acebutolol) to counteract inverted circadian rhythms [3][13].
Behavioral: Structured routines, communication therapy, and low-dose antipsychotics (e.g., risperidone) for aggression/self-injury [8][12][18].
Multidisciplinary care: Genetic, ENT, ophthalmologic, and developmental evaluations; scoliosis/obesity monitoring [1][6][17].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neurological diseases
Research Papers
102 drug discovery papers about Smith-Magenis syndrome, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
102 drug discovery papers about Smith-Magenis syndrome, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2025-05-29 | Retinoic Acid-Induced 1 Gene and Neuropsychiatric Diseases: A Systematic Review.
Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene implicated in a range of rare neuropsychiatric diseases. This review provides a comprehensive overview of RAI1's role, integrating both clinical and basic research on Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) while also summarising research progress on its involvement in spinocerebellar ataxia (SCA), autism spectrum disorder (ASD), schizophrenia, bipolar disorder and major depression. A systematic review of the literature was conducted using PubMed and EMBASE, following the PRISMA guidelines, with the protocol registered in PROSPERO (CRD42023474165). A total of 99 eligible studies on RAI1 were included. We presented detailed characterisations of SMS and PTLS patients, emphasising the crucial role of RAI1 haploinsufficiency and overexpression in their pathogenesis. Additionally, we summarised research progress on RAI1 in SCA, ASD, schizophrenia, bipolar disorder and major depression. Integrating findings from animal studies, particularly those examining the regulatory mechanisms of RAI1 in critical phenotypes, such as body weight, sleep and epilepsy, underscores the precise regulation of RAI1 expression in maintaining various nervous system functions. Overall, this review contributes to the identification of RAI1-related neuropsychiatric diseases, with a particular emphasis on enhancing clinical diagnosis of SMS and PTLS in developing countries.
2025-03-31 | Deletion Disorders
Cri-du-chat, Wolf-Hirschhorn, 22q11.2, Prader-Willi, and Smith-Magenis are neurogenetic disorders caused by a deletion of genetic material on one chromosome. Each condition is associated with a relatively well-defined developmental, physical health, and mental health phenotype. This chapter reviews the current state of knowledge regarding these deletion disorders with a focus on general and syndrome-specific assessment and intervention considerations.
2024-10-17 | Tunable, self-contained gene dosage control via proteolytic cleavage of CRISPR-Cas systems.
Gene therapy holds great therapeutic potential. Yet, controlling cargo expression in single cells is limited due to the variability of delivery methods. We implement an incoherent feedforward loop based on proteolytic cleavage of CRISPR-Cas activation or inhibition systems to reduce gene expression variability against the variability of vector delivery. We demonstrate dosage control for activation and inhibition, post-delivery tuning, and RNA-based delivery, for a genome-integrated marker. We then target the RAI1 gene, the haploinsufficiency and triplosensitivity of which cause two autism-related syndromes, Smith-Magenis-Syndrome (SMS) and Potocki-Lupski-Syndrome, respectively. We demonstrate dosage control for RAI1 activation in HEK293s, Neuro-2As, and mouse cortical neurons via AAVs and lentiviruses. Finally, we activate the intact RAI1 copy in SMS patient-derived cells to an estimated two-copy healthy range, avoiding the harmful three-copy regime. Our circuit paves the way for viable therapy in dosage-sensitive disorders, creating precise and tunable gene regulation systems for basic and translational research.
2024-07-03 | CRISPR-based genome editing of a diurnal rodent, Nile grass rat (Arvicanthis niloticus).
Diurnal and nocturnal mammals have evolved distinct pathways to optimize survival for their chronotype-specific lifestyles. Conventional rodent models, being nocturnal, may not sufficiently recapitulate the biology of diurnal humans in health and disease. Although diurnal rodents are potentially advantageous for translational research, until recently, they have not been genetically tractable. The present study aims to address this major limitation by developing experimental procedures necessary for genome editing in a well-established diurnal rodent model, the Nile grass rat (Arvicanthis niloticus). A superovulation protocol was established, which yielded nearly 30 eggs per female grass rat. Fertilized eggs were cultured in a modified rat 1-cell embryo culture medium (mR1ECM), in which grass rat embryos developed from the 1-cell stage into blastocysts. A CRISPR-based approach was then used for gene editing in vivo and in vitro, targeting Retinoic acid-induced 1 (Rai1), the causal gene for Smith-Magenis Syndrome, a neurodevelopmental disorder. The CRISPR reagents were delivered in vivo by electroporation using an improved Genome-editing via Oviductal Nucleic Acids Delivery (i-GONAD) method. The in vivo approach produced several edited founder grass rats with Rai1 null mutations, which showed stable transmission of the targeted allele to the next generation. CRISPR reagents were also microinjected into 2-cell embryos in vitro. Large deletion of the Rai1 gene was confirmed in 70% of the embryos injected, demonstrating high-efficiency genome editing in vitro. We have established a set of methods that enabled the first successful CRISPR-based genome editing in Nile grass rats. The methods developed will guide future genome editing of this and other diurnal rodent species, which will promote greater utility of these models in basic and translational research.
2024-05-03 | Retinoic Acid-Induced 1 gene variants associated with Smith–Magenis syndrome circadian phenotypes enriched in autism spectrum disorder: whole-genome sequencing study
Abstract Background This study aimed to characterize the frequency of RAI1 genetic aberrations associated with Smith–Magenis syndrome (SMS), in a large cohort of autism spectrum disorder (ASD) whole-genome sequencing samples. We aimed to determine the frequencies of RAI1 single-nucleotide variants (SNVs) and copy number variants (CNVs). Results We report a 2.5 × enrichment of the major deletion and a > 5 × enrichment of the frameshift variants as compared to the known prevalence of SMS 1/15,000. Additionally, we report a significant enrichment of RAI1 rare missense variants in ASD subjects with respect to controls (54 variants/6080 ASD subjects and 6 variants/2541 controls, p -value < 0.002, OR 3.78, CI 1.62–8–81). Conclusions The SMS phenotype including circadian dysregulation and associated sleep disturbances is mainly caused by RAI1 haploinsufficiency. Sleep disturbances as seen in SMS may overlap in ASD, especially in patients with consequential variants in RAI1 gene.
small molecules
2026-06-22 | Weight Loss Following Liraglutide Therapy in a Patient With Smith-Magenis Syndrome: A Case Report
This case reviews the use of a Glucagon-Like Peptide-1 Receptor Agonist (GLP1RA) in a young man presenting with excessive hunger and rapid weight gain compounded by an underlying rare form of genetic obesity, Smith-Magenis syndrome. The patient had, prior to presentation, seen an accelerated and persistent weight gain over the last five years despite attempts at portion control and behavior modification. Due to concerns of worsening metabolic disease, including prediabetes, dyslipidemia, and fatty liver disease, we started the patient on daily liraglutide and gradually titrated to the maximum dose over five months. He was able to tolerate the medication without severe gastrointestinal side effects, and alongside lifestyle and behavioral modifications, the patient lost 22.2 kg (49 lbs) over the course of 11 months. To our knowledge, there is only one other published case report documenting the use of GLP1RA therapy in a patient with Smith-Magenis syndrome.
2026-06-22 | RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression.
Human brain development proceeds on an unusually long timeline relative to other species, a feature that is thought to foster advanced cognitive abilities. Retinoic Acid Induced 1 ( RAI1 ) gene encodes a nucleosome-binding protein haploinsufficient in Smith-Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive impairment with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome analysis during in vitro cortical development revealed that RAI1 deficiency accelerates developmental gene expression progression, including the precocious induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1- deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.
2026-06-05 | Tirzepatide for weight and behavior management in a patient with Smith-Magenis syndrome.
Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. While dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated efficacy in the general population, their use in patients with SMS has not been described. We report the case of a 31-year-old woman with SMS (17p11.2 deletion) treated with tirzepatide, a dual GIP/GLP-1 receptor agonist. The patient presented with lifelong obesity (body mass index [BMI] 32.0-32.9 kg/m2 in adulthood) and aggressive behaviors refractory to standard management. Following initiation of tirzepatide, titrated to 5 mg weekly, she achieved 9.4% weight loss (7.3 kg) over 10 months, along with improvement in fasting glucose levels. Concurrently, caregivers reported notable behavioral improvements, including reduced food-seeking behavior and impulsivity. Quantitative analysis demonstrated a significant reduction in aggression. The treatment was well tolerated. This case suggests that tirzepatide may represent a promising therapeutic option for SMS, targeting both metabolic and central nervous system pathways involved in its phenotype.
2026-05-18 | Melatonin Levels in 89 Individuals With Smith Magenis Syndrome.
In patients with Smith-Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT levels, resulting in even more sleep disorders. We therefore retrospectively evaluated the MT data of 89 SMS patients. Mean MT levels in participants on exogenous MT were significantly higher than in participants that did not use MT (p = < 0.0001). In 9 participants with very high MT levels, these dropped significantly after discontinuation of exogenous MT (p = 0.0037). In 12 participants, MT levels were significantly higher after MT therapy start compared to MT levels before MT start (p = 0.028). MT is catabolized principally by the CYP1A2 enzyme, with a half-life of about 40 min. CYP1A2 genotyping was performed in five participants with high MT levels during MT use. Although clinically suspected to be a poor CYP1A2 metabolizer, all five turned out to have haplotype CYP1A2*1F, which is associated with increased enzyme activity. This shows that genotyping of CYP1A2 is not suitable to estimate the level of CYP1A2 enzyme activity. When prescribing MT, it is strongly recommended to measure a MT level prior to treatment in order to determine the dose to be given. Checks of the MT level during treatment are necessary due to the frequent occurrence of poor CYP1A2 metabolism. Since CYP1A2 genotyping does not provide adequate information about the level of CYP1A2 enzyme activity, we propose a simple way to determine CYP1A2 phenotype.
2026-01-01 | P100: Copy-number loss of 17p11.2 with a TMEM127 pathogenic variant: A unique case of combined Smith-Magenis, Birt-Hogg-Dubé, and hereditary paraganglioma-pheochromocytoma syndromes
p.Val989Ter).This variant was confirmed via clinical testing and also found to be paternally inherited.Pertinent family history includes a 35-year-old paternal aunt diagnosed with breast cancer in her early 30s.Following resection, Patient B continued on levetiracetam and was seizure-free for nearly 3 months but was transitioned to oxcarbazepine due to intolerable side effects.Thirteen months post-surgery, there is no evidence of tumor recurrence, although he continues to experience intermittent seizures.
antibodies
2026-01-01 | Immunodeficiency in a case diagnosed with Smith-Magenissyndrome
Smith-Magenis syndrome is a complex genetic disorder caused by deletion or mutation of the retinoic acid-induced 1 gene located primarily on chromosome 17p11.2. This syndrome is characterized by a series of physical, developmental, and behavioral abnormalities, including immune deficiencies presenting as recurrent infections. We report a 4-year-old male patient who presented to the pediatric immunology-allergy clinic with the complaint of frequent illnesses with the diagnosis of Smith-Magenis syndrome. As a result of the clinical and laboratory examinations, the patient was diagnosed with IgG subclass deficiency and was started on intravenous immunoglobulin replacement therapy. Recurrent infections associated with antibody deficiencies represent a very rare critical aspect of the syndrome that requires further investigation in the clinical setting. The complexity of Smith-Magenis syndrome necessitates an integrated healthcare strategy to provide holistic management of this multifaceted condition and highlights the need for ongoing research into its genetic, immunological, and neurodevelopmental dimensions. This rare case report sheds light on further research and provides a better understanding of the clinical presentation of the syndrome.
2025-10-01 | S4874 Double Trouble: Managing Therapy-Refractory Crohn’s Disease in a Patient With Smith-Magenis Syndrome
Introduction: Pediatric-onset inflammatory bowel disease (IBD) is increasingly recognized to have an underlying genetic component, particularly in cases that are non-responsive to conventional therapies. We report a case of a 19-year-old woman with early-onset, treatment-refractory Crohn’s disease with intellectual disability and growth failure. Genetic analysis revealed a heterozygous chromosomal deletion, raising the possibility of monogenic or genetically influenced IBD phenotype. Case Description/Methods: A 19-year-old woman, born to non-consanguineous parents, at term, had facial dysmorphism, intellectual disability and short stature, which was not evaluated during childhood. She presented with chronic bloody diarrhea, tenesmus and fatigue since the age of 10. Colonoscopy revealed linear, deep ulcers and a stricture in the rectosigmoid region. Biopsies revealed features of chronic active colitis. Computed tomography enterography showed pancolitis with loss of haustrations, ileocecal junction thickening, and mesenteric fat stranding. A diagnosis of Crohn’s colitis was made, and patient initiated on oral corticosteroids followed by advanced therapy (infliximab). Simultaneously, genetic testing with whole exome sequencing was done, which revealed a heterozygous missense variant in SLC39A4, and heterozygous deletion on chromosome 17 encompassing multiple genes. The patient subsequently had secondary loss of response to Infliximab and in August 2024, she was re-admitted with similar complaints and repeat sigmoidoscopy showed persistent ulcerations and narrowing in the rectosigmoid region. She was started on adalimumab, however, she has had only partial resolution in symptoms with persistent anemia and hypoalbuminemia. She is now being planned for combined advanced therapy with addition of ustekinumab. Discussion: This case illustrates diagnostic and therapeutic complexities in managing pediatric-onset Crohn’s disease, especially when associated with systemic clinical findings. The deletion on chromosome 17 leads to loss of genes including RAI1, SREBF1, TNFRSF13B. RAI1 deletion, which is causative of Smith-Magenis syndrome, is associated with intellectual disability, including speech and motor delay, craniofacial and skeletal anomalies and sleep disturbance. However, we could not find any case report linking IBD with Smith-Magenis syndrome. This case underscores the need for an evolving understanding of monogenic and genetically influenced IBD, which may pave the way for more targeted interventions in these patients.
2018-05-10 | Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies.
Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy. The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods. We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays. Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens. Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.
2011-11-01 | Determining true HER2 gene status in breast cancers with polysomy by using alternative chromosome 17 reference genes: implications for anti-HER2 targeted therapy.
Purpose The ratio of human epidermal growth factor receptor 2 (HER2) to CEP17 by fluorescent in situ hybridization (FISH) with the centromeric probe CEP17 is used to determine HER2 gene status in breast cancer. Increases in CEP17 copy number have been interpreted as representing polysomy 17. However, pangenomic studies have demonstrated that polysomy 17 is rare. This study tests the hypothesis that the use of alternative chromosome 17 reference genes might more accurately assess true HER2 gene status. Patients and Methods In all, 171 patients with breast cancer who had HER2 FISH that had increased mean CEP17 copy numbers (> 2.6) were selected for additional chromosome 17 studies that used probes for Smith-Magenis syndrome (SMS), retinoic acid receptor alpha (RARA), and tumor protein p53 (TP53) genes. A eusomic copy number exhibited in one or more of these loci was used to calculate a revised HER2-to-chromosome-17 ratio by using the eusomic gene locus as the reference. Results Of 132 cases classified as nonamplified on the basis of their HER2:CEP17 ratios, 58 (43.9%) were scored as amplified by using alternative chromosome 17 reference gene probes, and 13 (92.9%) of 14 cases scored as equivocal were reclassified as amplified. Among the cases with mean HER2 copy number of 4 to 6, 41 (47.7%) of 86 had their HER2 gene status upgraded from nonamplified to amplified, and four (4.7%) of 86 were upgraded from equivocal to amplified. Conclusion Our results support the findings of recent pangenomic studies that true polysomy 17 is uncommon. Additional FISH studies that use probes to the SMS, RARA, and TP53 genes are an effective way to determine the true HER2 amplification status in patients with polysomy 17 and they have important potential implications for guiding HER2-targeted therapy in breast cancer.
gene therapies
2025-05-29 | Retinoic Acid-Induced 1 Gene and Neuropsychiatric Diseases: A Systematic Review.
Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene implicated in a range of rare neuropsychiatric diseases. This review provides a comprehensive overview of RAI1's role, integrating both clinical and basic research on Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) while also summarising research progress on its involvement in spinocerebellar ataxia (SCA), autism spectrum disorder (ASD), schizophrenia, bipolar disorder and major depression. A systematic review of the literature was conducted using PubMed and EMBASE, following the PRISMA guidelines, with the protocol registered in PROSPERO (CRD42023474165). A total of 99 eligible studies on RAI1 were included. We presented detailed characterisations of SMS and PTLS patients, emphasising the crucial role of RAI1 haploinsufficiency and overexpression in their pathogenesis. Additionally, we summarised research progress on RAI1 in SCA, ASD, schizophrenia, bipolar disorder and major depression. Integrating findings from animal studies, particularly those examining the regulatory mechanisms of RAI1 in critical phenotypes, such as body weight, sleep and epilepsy, underscores the precise regulation of RAI1 expression in maintaining various nervous system functions. Overall, this review contributes to the identification of RAI1-related neuropsychiatric diseases, with a particular emphasis on enhancing clinical diagnosis of SMS and PTLS in developing countries.
2025-03-31 | Deletion Disorders
Cri-du-chat, Wolf-Hirschhorn, 22q11.2, Prader-Willi, and Smith-Magenis are neurogenetic disorders caused by a deletion of genetic material on one chromosome. Each condition is associated with a relatively well-defined developmental, physical health, and mental health phenotype. This chapter reviews the current state of knowledge regarding these deletion disorders with a focus on general and syndrome-specific assessment and intervention considerations.
2024-10-17 | Tunable, self-contained gene dosage control via proteolytic cleavage of CRISPR-Cas systems.
Gene therapy holds great therapeutic potential. Yet, controlling cargo expression in single cells is limited due to the variability of delivery methods. We implement an incoherent feedforward loop based on proteolytic cleavage of CRISPR-Cas activation or inhibition systems to reduce gene expression variability against the variability of vector delivery. We demonstrate dosage control for activation and inhibition, post-delivery tuning, and RNA-based delivery, for a genome-integrated marker. We then target the RAI1 gene, the haploinsufficiency and triplosensitivity of which cause two autism-related syndromes, Smith-Magenis-Syndrome (SMS) and Potocki-Lupski-Syndrome, respectively. We demonstrate dosage control for RAI1 activation in HEK293s, Neuro-2As, and mouse cortical neurons via AAVs and lentiviruses. Finally, we activate the intact RAI1 copy in SMS patient-derived cells to an estimated two-copy healthy range, avoiding the harmful three-copy regime. Our circuit paves the way for viable therapy in dosage-sensitive disorders, creating precise and tunable gene regulation systems for basic and translational research.
2024-07-03 | CRISPR-based genome editing of a diurnal rodent, Nile grass rat (Arvicanthis niloticus).
Diurnal and nocturnal mammals have evolved distinct pathways to optimize survival for their chronotype-specific lifestyles. Conventional rodent models, being nocturnal, may not sufficiently recapitulate the biology of diurnal humans in health and disease. Although diurnal rodents are potentially advantageous for translational research, until recently, they have not been genetically tractable. The present study aims to address this major limitation by developing experimental procedures necessary for genome editing in a well-established diurnal rodent model, the Nile grass rat (Arvicanthis niloticus). A superovulation protocol was established, which yielded nearly 30 eggs per female grass rat. Fertilized eggs were cultured in a modified rat 1-cell embryo culture medium (mR1ECM), in which grass rat embryos developed from the 1-cell stage into blastocysts. A CRISPR-based approach was then used for gene editing in vivo and in vitro, targeting Retinoic acid-induced 1 (Rai1), the causal gene for Smith-Magenis Syndrome, a neurodevelopmental disorder. The CRISPR reagents were delivered in vivo by electroporation using an improved Genome-editing via Oviductal Nucleic Acids Delivery (i-GONAD) method. The in vivo approach produced several edited founder grass rats with Rai1 null mutations, which showed stable transmission of the targeted allele to the next generation. CRISPR reagents were also microinjected into 2-cell embryos in vitro. Large deletion of the Rai1 gene was confirmed in 70% of the embryos injected, demonstrating high-efficiency genome editing in vitro. We have established a set of methods that enabled the first successful CRISPR-based genome editing in Nile grass rats. The methods developed will guide future genome editing of this and other diurnal rodent species, which will promote greater utility of these models in basic and translational research.
2024-05-03 | Retinoic Acid-Induced 1 gene variants associated with Smith–Magenis syndrome circadian phenotypes enriched in autism spectrum disorder: whole-genome sequencing study
Abstract Background This study aimed to characterize the frequency of RAI1 genetic aberrations associated with Smith–Magenis syndrome (SMS), in a large cohort of autism spectrum disorder (ASD) whole-genome sequencing samples. We aimed to determine the frequencies of RAI1 single-nucleotide variants (SNVs) and copy number variants (CNVs). Results We report a 2.5 × enrichment of the major deletion and a > 5 × enrichment of the frameshift variants as compared to the known prevalence of SMS 1/15,000. Additionally, we report a significant enrichment of RAI1 rare missense variants in ASD subjects with respect to controls (54 variants/6080 ASD subjects and 6 variants/2541 controls, p -value < 0.002, OR 3.78, CI 1.62–8–81). Conclusions The SMS phenotype including circadian dysregulation and associated sleep disturbances is mainly caused by RAI1 haploinsufficiency. Sleep disturbances as seen in SMS may overlap in ASD, especially in patients with consequential variants in RAI1 gene.
small molecules
2026-06-22 | Weight Loss Following Liraglutide Therapy in a Patient With Smith-Magenis Syndrome: A Case Report
This case reviews the use of a Glucagon-Like Peptide-1 Receptor Agonist (GLP1RA) in a young man presenting with excessive hunger and rapid weight gain compounded by an underlying rare form of genetic obesity, Smith-Magenis syndrome. The patient had, prior to presentation, seen an accelerated and persistent weight gain over the last five years despite attempts at portion control and behavior modification. Due to concerns of worsening metabolic disease, including prediabetes, dyslipidemia, and fatty liver disease, we started the patient on daily liraglutide and gradually titrated to the maximum dose over five months. He was able to tolerate the medication without severe gastrointestinal side effects, and alongside lifestyle and behavioral modifications, the patient lost 22.2 kg (49 lbs) over the course of 11 months. To our knowledge, there is only one other published case report documenting the use of GLP1RA therapy in a patient with Smith-Magenis syndrome.
2026-06-22 | RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression.
Human brain development proceeds on an unusually long timeline relative to other species, a feature that is thought to foster advanced cognitive abilities. Retinoic Acid Induced 1 ( RAI1 ) gene encodes a nucleosome-binding protein haploinsufficient in Smith-Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive impairment with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome analysis during in vitro cortical development revealed that RAI1 deficiency accelerates developmental gene expression progression, including the precocious induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1- deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.
2026-06-05 | Tirzepatide for weight and behavior management in a patient with Smith-Magenis syndrome.
Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. While dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated efficacy in the general population, their use in patients with SMS has not been described. We report the case of a 31-year-old woman with SMS (17p11.2 deletion) treated with tirzepatide, a dual GIP/GLP-1 receptor agonist. The patient presented with lifelong obesity (body mass index [BMI] 32.0-32.9 kg/m2 in adulthood) and aggressive behaviors refractory to standard management. Following initiation of tirzepatide, titrated to 5 mg weekly, she achieved 9.4% weight loss (7.3 kg) over 10 months, along with improvement in fasting glucose levels. Concurrently, caregivers reported notable behavioral improvements, including reduced food-seeking behavior and impulsivity. Quantitative analysis demonstrated a significant reduction in aggression. The treatment was well tolerated. This case suggests that tirzepatide may represent a promising therapeutic option for SMS, targeting both metabolic and central nervous system pathways involved in its phenotype.
2026-05-18 | Melatonin Levels in 89 Individuals With Smith Magenis Syndrome.
In patients with Smith-Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT levels, resulting in even more sleep disorders. We therefore retrospectively evaluated the MT data of 89 SMS patients. Mean MT levels in participants on exogenous MT were significantly higher than in participants that did not use MT (p = < 0.0001). In 9 participants with very high MT levels, these dropped significantly after discontinuation of exogenous MT (p = 0.0037). In 12 participants, MT levels were significantly higher after MT therapy start compared to MT levels before MT start (p = 0.028). MT is catabolized principally by the CYP1A2 enzyme, with a half-life of about 40 min. CYP1A2 genotyping was performed in five participants with high MT levels during MT use. Although clinically suspected to be a poor CYP1A2 metabolizer, all five turned out to have haplotype CYP1A2*1F, which is associated with increased enzyme activity. This shows that genotyping of CYP1A2 is not suitable to estimate the level of CYP1A2 enzyme activity. When prescribing MT, it is strongly recommended to measure a MT level prior to treatment in order to determine the dose to be given. Checks of the MT level during treatment are necessary due to the frequent occurrence of poor CYP1A2 metabolism. Since CYP1A2 genotyping does not provide adequate information about the level of CYP1A2 enzyme activity, we propose a simple way to determine CYP1A2 phenotype.
2026-01-01 | P100: Copy-number loss of 17p11.2 with a TMEM127 pathogenic variant: A unique case of combined Smith-Magenis, Birt-Hogg-Dubé, and hereditary paraganglioma-pheochromocytoma syndromes
p.Val989Ter).This variant was confirmed via clinical testing and also found to be paternally inherited.Pertinent family history includes a 35-year-old paternal aunt diagnosed with breast cancer in her early 30s.Following resection, Patient B continued on levetiracetam and was seizure-free for nearly 3 months but was transitioned to oxcarbazepine due to intolerable side effects.Thirteen months post-surgery, there is no evidence of tumor recurrence, although he continues to experience intermittent seizures.
antibodies
2026-01-01 | Immunodeficiency in a case diagnosed with Smith-Magenissyndrome
Smith-Magenis syndrome is a complex genetic disorder caused by deletion or mutation of the retinoic acid-induced 1 gene located primarily on chromosome 17p11.2. This syndrome is characterized by a series of physical, developmental, and behavioral abnormalities, including immune deficiencies presenting as recurrent infections. We report a 4-year-old male patient who presented to the pediatric immunology-allergy clinic with the complaint of frequent illnesses with the diagnosis of Smith-Magenis syndrome. As a result of the clinical and laboratory examinations, the patient was diagnosed with IgG subclass deficiency and was started on intravenous immunoglobulin replacement therapy. Recurrent infections associated with antibody deficiencies represent a very rare critical aspect of the syndrome that requires further investigation in the clinical setting. The complexity of Smith-Magenis syndrome necessitates an integrated healthcare strategy to provide holistic management of this multifaceted condition and highlights the need for ongoing research into its genetic, immunological, and neurodevelopmental dimensions. This rare case report sheds light on further research and provides a better understanding of the clinical presentation of the syndrome.
2025-10-01 | S4874 Double Trouble: Managing Therapy-Refractory Crohn’s Disease in a Patient With Smith-Magenis Syndrome
Introduction: Pediatric-onset inflammatory bowel disease (IBD) is increasingly recognized to have an underlying genetic component, particularly in cases that are non-responsive to conventional therapies. We report a case of a 19-year-old woman with early-onset, treatment-refractory Crohn’s disease with intellectual disability and growth failure. Genetic analysis revealed a heterozygous chromosomal deletion, raising the possibility of monogenic or genetically influenced IBD phenotype. Case Description/Methods: A 19-year-old woman, born to non-consanguineous parents, at term, had facial dysmorphism, intellectual disability and short stature, which was not evaluated during childhood. She presented with chronic bloody diarrhea, tenesmus and fatigue since the age of 10. Colonoscopy revealed linear, deep ulcers and a stricture in the rectosigmoid region. Biopsies revealed features of chronic active colitis. Computed tomography enterography showed pancolitis with loss of haustrations, ileocecal junction thickening, and mesenteric fat stranding. A diagnosis of Crohn’s colitis was made, and patient initiated on oral corticosteroids followed by advanced therapy (infliximab). Simultaneously, genetic testing with whole exome sequencing was done, which revealed a heterozygous missense variant in SLC39A4, and heterozygous deletion on chromosome 17 encompassing multiple genes. The patient subsequently had secondary loss of response to Infliximab and in August 2024, she was re-admitted with similar complaints and repeat sigmoidoscopy showed persistent ulcerations and narrowing in the rectosigmoid region. She was started on adalimumab, however, she has had only partial resolution in symptoms with persistent anemia and hypoalbuminemia. She is now being planned for combined advanced therapy with addition of ustekinumab. Discussion: This case illustrates diagnostic and therapeutic complexities in managing pediatric-onset Crohn’s disease, especially when associated with systemic clinical findings. The deletion on chromosome 17 leads to loss of genes including RAI1, SREBF1, TNFRSF13B. RAI1 deletion, which is causative of Smith-Magenis syndrome, is associated with intellectual disability, including speech and motor delay, craniofacial and skeletal anomalies and sleep disturbance. However, we could not find any case report linking IBD with Smith-Magenis syndrome. This case underscores the need for an evolving understanding of monogenic and genetically influenced IBD, which may pave the way for more targeted interventions in these patients.
2018-05-10 | Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies.
Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy. The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods. We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays. Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens. Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.
2011-11-01 | Determining true HER2 gene status in breast cancers with polysomy by using alternative chromosome 17 reference genes: implications for anti-HER2 targeted therapy.
Purpose The ratio of human epidermal growth factor receptor 2 (HER2) to CEP17 by fluorescent in situ hybridization (FISH) with the centromeric probe CEP17 is used to determine HER2 gene status in breast cancer. Increases in CEP17 copy number have been interpreted as representing polysomy 17. However, pangenomic studies have demonstrated that polysomy 17 is rare. This study tests the hypothesis that the use of alternative chromosome 17 reference genes might more accurately assess true HER2 gene status. Patients and Methods In all, 171 patients with breast cancer who had HER2 FISH that had increased mean CEP17 copy numbers (> 2.6) were selected for additional chromosome 17 studies that used probes for Smith-Magenis syndrome (SMS), retinoic acid receptor alpha (RARA), and tumor protein p53 (TP53) genes. A eusomic copy number exhibited in one or more of these loci was used to calculate a revised HER2-to-chromosome-17 ratio by using the eusomic gene locus as the reference. Results Of 132 cases classified as nonamplified on the basis of their HER2:CEP17 ratios, 58 (43.9%) were scored as amplified by using alternative chromosome 17 reference gene probes, and 13 (92.9%) of 14 cases scored as equivocal were reclassified as amplified. Among the cases with mean HER2 copy number of 4 to 6, 41 (47.7%) of 86 had their HER2 gene status upgraded from nonamplified to amplified, and four (4.7%) of 86 were upgraded from equivocal to amplified. Conclusion Our results support the findings of recent pangenomic studies that true polysomy 17 is uncommon. Additional FISH studies that use probes to the SMS, RARA, and TP53 genes are an effective way to determine the true HER2 amplification status in patients with polysomy 17 and they have important potential implications for guiding HER2-targeted therapy in breast cancer.
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Drug Discovery Landscape
6 orphan drug designations for Smith-Magenis syndrome, including 2 approved therapies.
6 orphan drug designations for Smith-Magenis syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Tasimelteon | small molecules | EMA | 2023-10-13 | — | Vanda Pharmaceuticals Netherlands B.V. |
melatonin | small molecules | FDA | 2016-11-03 | — | WORPHMED Srl |
Acebutolol hydrochloride | small molecules | EMA | 2016-10-14 | — | Worphmed Srl |
Melatonin | small molecules | EMA | 2016-10-14 | — | Worphmed Srl |
tasimelteon [Hetlioz LQ] | small molecules | FDA | 2010-04-30 | 2020-12-01 | Vanda Pharmaceuticals, Inc. |
tasimelteon [Hetlioz] | small molecules | FDA | 2010-04-30 | 2020-12-01 | Vanda Pharmaceuticals, Inc. |
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