2026-07-09 | TANGO2-related metabolic encephalopathy-arrhythmia syndrome unmasked in 22q11.2 deletion syndrome: hemizygous pathogenic variant, complex phenotype modified by two genetic conditions, and implications for proactive crisis prevention: a case report.
TANGO2 deficiency disorder is an ultra-rare autosomal recessive condition characterized by life-threatening metabolic crises with rhabdomyolysis and cardiac arrhythmias. Patients with 22q11.2 deletion syndrome are at increased risk when a pathogenic variant occurs in the remaining allele, yet this dual diagnosis remains underrecognized as clinicians often attribute all manifestations to the primary genetic condition. We report a case of a child with confirmed 22q11.2 deletion syndrome in whom a coexisting variant in the TANGO2 gene was diagnosed at the age of 5 after first metabolic crisis with rhabdomyolysis. A girl with 22q11.2 deletion syndrome diagnosed in infancy exhibited global developmental delay and chronic excessive sleepiness attributed to her established diagnosis. At age 5, she experienced her first metabolic crisis during pneumonia with severe rhabdomyolysis (creatine kinase >100,000 U/L), features inconsistent with isolated 22q11.2 deletion syndrome. Two additional metabolic crises occurred at age 7 before exome sequencing revealed a hemizygous TANGO2 variant c.536G>A, confirming TANGO2 deficiency. A previously unreported hemizygous missense variant c.536G>A (p.Gly138Glu) in the TANGO2 gene (NM_152906.7) was identified and verified by NGS-based deep amplicon sequencing and Sanger direct sequencing; segregation analysis confirmed paternal inheritance with the maternal allele deleted within the 22q11.2 region. Following diagnosis, B-vitamin supplementation, coenzyme Q10, L-carnitine, and gastrostomy tube placement were initiated to ensure consistent hydration and prevent prolonged periods without nutrition, a known crisis trigger. The patient achieved 4 years of crisis-free stability with reduced daytime sleepiness. At age 11, she remains stable without further crises. This case demonstrates that exome sequencing should be pursued early when atypical features emerge in patients with established genetic diagnoses. The sustained crisis-free period following gastrostomy placement supports proactive nutritional intervention in TANGO2 patients with feeding difficulties. Clinicians must recognize that microdeletion syndrome patients can harbor variants unmasking additional autosomal recessive conditions requiring distinct management.
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2026-06-27 | Neuropsychiatric Disease Mechanisms and Interventions. from 22q11.2 Deletion Syndrome Experimental Studies.
A high genetic predisposition for neuropsychiatric disorders, such as schizophrenia and autism spectrum disorders (ASDs), is 22q11.2 deletion syndrome (22q11DS), caused by a hemizygous microdeletion in the q-arm of human chromosome 22. The deletion most often spans a 3Mb region, with variable breakpoints ranging from 1.5-3Mb. Experimental studies on 22q11DS have revealed the pathophysiology of neuropsychiatric disorders and also identified various interventional and rescue strategies. Herein, we review these strategies by grouping the studies into three main mechanistic categories: (i) microRNA (miR)-mediated, (ii) mitochondrial, and (iii) neural circuit deficits in polygenic deletion, and also briefly describe a few other monogenic mechanisms implicated. Haploinsufficiency of Dgcr8, a 22q11DS gene involved in miR processing, forms the center of miR-mediated mechanisms and rescuing consequent pathophysiology rely on age-dependent, brain-region specific or global replenishment of miRs or their targets. Seven genes in the 22q11.2 genomic region encode mitochondrial proteins and approaches to mitigate these gene deficiencies concentrate on the respective mitochondrial functions affected. We briefly describe other potential monogenic mechanisms for intervention including transcriptional regulation, synaptic release, catecholamine metabolism, and cell adhesion, represented by Tbx1, Sept5, COMT, Arvcf, and Cldn5. We also give examples of how the multifaceted pathophysiological mechanisms and rescue strategies can have convergent effects at the molecular, synaptic, cellular and circuit levels. Based on the experimental interventions identified in the 22q11DS studies, we inform on the supportive therapies possible now and the future potential of curative interventions.
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2026-06-19 | An antioxidant therapy elicits distinct transcriptome responses in 22q11-deleted upper layer cortical projection neurons.
We characterized in vitro and in vivo responses to the antioxidant N-acetyl cysteine (NAC), which in the 22q11.2 Deletion Syndrome LgDel mouse model restores growth and connectivity of developing upper layer cortical projection neurons (Layer 2/3 PNs) and improves cognitive performance. NAC ameliorates L 2/3 PN developmental pathology without restoring wild type (WT) growth patterns or expression levels of downstream targets of 22q11-deleted genes. Instead, novel neuronal growth and antioxidant defense genes are differentially expressed compared to LgDel or WT: some generally NAC-regulated, others responsive only in the context of 22q11 deletion. NAC also elicits novel growth and antioxidant defense gene expression in differentiating 22q11-deleted L 2/3 PNs in postnatal LgDel mouse cortex rather than restoring 22q11 downstream targets to WT levels; however, these L 2/3 PN-selective in vivo changes differ substantially from those in primary culture. Thus, the NAC therapeutic response that diminishes oxidative stress-related L 2/3 PN developmental circuit and behavioral pathology due to 22q11 deletion has a distinct in vivo signature.
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