👤 Bulent Cetin

Myasthenia gravis (MG) is a disorder of the neuromuscular junction, typically associated with autoantibodies (Abs) that impair neuromuscular transmission. However, approximately 10% of cases are seronegative. Emerging evidence suggests that seronegative MG (SNMG) may be mimicked by hereditary conditions, particularly congenital myasthenic syndromes (CMSs), which require different treatments. In this study, we aimed to determine the proportion of CMS among patients diagnosed with SNMG. We used whole-exome sequencing (WES) in adult patients (aged ≥18 years) diagnosed with SNMG who were enrolled at 3 Austrian tertiary neuromuscular centers between August 2022 and January 2024. Genetic testing was conducted in individuals who remained seronegative after comprehensive serologic testing to exclude Abs against (clustered) acetylcholine receptors, muscle-specific kinase, lipoprotein receptor-related protein 4, and voltage-gated calcium channels. Moreover, we aimed to analyze clinical and demographic factors associated with the likelihood of receiving a molecular diagnosis. A total of 50 patients with SNMG (35 [70%] female) were referred for exome-based genetic screening. The median age at disease onset was 35 years (interquartile range 24.0-46.0 years). Seven patients (14%) were genetically diagnosed with CMS through WES (4 with Our findings provide evidence that a considerable proportion of patients diagnosed with SNMG have an underlying hereditary etiology. Notably, a (subjective) response to immunotherapies does not exclude a molecular CMS diagnosis. In conclusion, offering genetic testing to seronegative patients with myasthenic syndromes may have profound therapeutic implications. Show less

Koolen-de Vries syndrome (KdVS) is a rare multisystemic disorder caused by a microdeletion on chromosome 17q21.31 including KANSL1 gene or intragenic pathogenic variants in KANSL1 gene. Here, we describe the clinical and genetic spectrum of eight Turkish children with KdVS due to a de novo 17q21.31 deletion, and report on several rare/new conditions. Eight patients from unrelated families aged between 17 months and 19 years enrolled in this study. All patients evaluated by a clinical geneticist, and the clinical diagnosis were confirmed by molecular karyotyping. KdVS patients had some common distinctive facial features. All patients had neuromotor retardation, and speech and language delay. Epilepsy, structural brain anomalies, ocular, ectodermal, and musculoskeletal findings, and friendly personality were remarkable in more than half of the patients. Hypertension, hypothyroidism, celiac disease, and postaxial polydactyly were among the rare/new conditions. Our study contributes to the clinical spectrum of patients with KdVS, while also provide a review by comparing them with previous cohort studies. Show less

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted. We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria. Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0-4.3) in Austria. The most frequent genetic etiology was CHRNE (n = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 (n = 4), RAPSN (n = 3), COLQ (n = 2), GMPPB (n = 2), CHAT (n = 1), COL13A1 (n = 1), MUSK (n = 1) and AGRN (n = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients. Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype-phenotype correlations that may help to improve the diagnostic approach and patient management. Show less

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. Show less