Clinical Variability and Genotype‐Driven Outcomes in CHRND‐Related Congenital Myasthenic Syndrome

Congenital myasthenic syndromes in Türkiye: genetic and clinical spectrum revisited in a nationwide pediatric cohort.

Congenital myasthenic syndromes (CMS) are inherited disorders caused by defects in proteins essential for neuromuscular transmission. In this nationwide, multicenter retrospective study, we analyzed 133 genetically confirmed CMS cases from 118 unrelated families between 2017 and 2024 across 28 centers in Türkiye. Clinical, electrophysiological, and genetic data were collected from medical records. In addition, we performed a PubMed-based review of previously reported genetically confirmed Turkish CMS cases to place our findings in a broader national context. The median age at symptom onset, and the median diagnostic delay were 6 months and 24 months, respectively. Ocular involvement was the most common clinical feature, followed by respiratory and bulbar involvement. High consanguinity (82%) contributed to a predominance of homozygous variants. Variants were identified in 16 CMS-associated genes, with COLQ (34.6%), CHRNE (24.1%), and CHAT (12.8%) being the most frequent. Postsynaptic CMS was the most common anatomical subgroup. Eighteen novel variants across 11 genes expanded the mutational spectrum of CMS. Review of 23 previously published studies from Türkiye identified 139 additional genetically confirmed cases, showing a broadly similar genetic distribution, with CHRNE and COLQ predominating, followed by CHAT, whereas other CMS-associated genes were reported only sporadically. >These findings define the clinical and genetic landscape of CMS in Türkiye and, together with previously published Turkish cases, provide a broad national overview based on 272 genetically confirmed cases. The results highlight the major contribution of a limited number of genes and underscore the importance of early molecular diagnosis in a population with high consanguinity.

First Korean Case of DOK7 Congenital Myasthenic Syndrome Responsive to Ephedrine Therapy

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic neuromuscular disorders caused by pathogenic variants in genes encoding proteins essential for neuromuscular junction development and function. Downstream of tyrosine kinase 7 (DOK7)-related CMS has been reported frequently in Europe, North America, and Japan, but not in Korea. A 7-year-old girl presented with gait disturbance, frequent falls, and difficulty climbing stairs, which had begun at 4 years of age. Examination revealed mild symmetric proximal weakness without ocular or bulbar involvement, and her serum creatine kinase level was normal. She was initially diagnosed with congenital myopathy. At 24 years of age, whole-exome sequencing identified compound heterozygous pathogenic variants in DOK7 (c.[539G>C];[1124_1127dup]), confirming DOK7 CMS. On clinical re-evaluation, she had stable proximal weakness, and repetitive nerve stimulation demonstrated a significant decremental response in the trapezius muscle. After 1 month of oral ephedrine therapy at 50 mg/day, her endurance and stair-climbing ability improved substantially. We report the first Korean case of DOK7 CMS with a favorable therapeutic response to ephedrine, emphasizing the need to consider CMS in the differential diagnosis of congenital myopathy.

Molecular and clinical heterogeneity in an Iranian case series of Joubert syndrome

This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies.

Allgrove syndrome in Colombia: clinical characterization and evidence of a possible founder effect

Pragmatic Phenotype–Electrophysiology–Genomics Integration in Pediatric Congenital Myasthenic Syndromes: Insights From 36 Patients in a Single‐Center Study in China

ABSTRACT Aims To characterize the clinical, electrophysiological, and genetic spectrum of pediatric CMS and evaluate genotype‐informed outcomes using an integrated phenotype–electrophysiology–genomics approach. Methods We retrospectively reviewed 36 pediatric CMS patients evaluated at a single center between 2015 and 2025. Clinical features, RNS, targeted NGS/WES variants, ventilator use, treatments, ACMG/AMP classifications, and MG‐ADL outcomes were analyzed. Results Of 36 patients, 28 (77.8%) developed symptoms in the neonatal period or infancy. Biallelic variants involved 17 CMS genes; postsynaptic CMS was most common (55.6%, 20/36). COLQ and CHRNE were the most frequent genes (13.9%, 5/36 each), followed by CHAT (11.1%, 4/36). VUS were detected in 19 patients (52.8%, 19/36), including 8 with biallelic VUS supported by phenotype, neuromuscular transmission findings, treatment response, and follow‐up. RNS showed a ≥ 10% decrement in 16/21 tested patients (76.2%). CHAT‐CMS was associated with higher ventilator use (3/4 vs. 6/32; p = 0.041) and early mortality (3/4 vs. 1/32; p = 0.002). Median MG‐ADL improved from 5 to 3 after genotype‐informed therapy. Conclusion Pediatric CMS shows marked genetic heterogeneity and frequent VUS‐related uncertainty. Integrating phenotype, electrophysiology, and genomics supports diagnosis and mechanism‐guided therapy. CHAT‐CMS is high risk for early respiratory failure and mortality.

Clinical and Genetic Profile of One Molecularly Confirmed and One Clinically Suspected Case of LZTR1 ‐Related Noonan Syndrome

Two unrelated female pediatric patients evaluated for LZTR1‐related NS following whole‐exome sequencing are reported to illustrate the marked phenotypic variability of LZTR1‐related NS and underscore that, while cardiac defects may be absent in some individuals, appropriate cardiac surveillance remains necessary.