Clinical Genetics最新文献

Next-generation sequencing is advancing in low- and middle-income countries, but accessibility remains limited. In Pakistan, many members of the Pashtun population practice familial marriage and maintain distinct socio-cultural traditions, isolating them from other ethnic groups. As a result, they may harbor genetic variants that could unveil new gene-disease associations. To investigate the genetic basis of epilepsy in the Pashtun community we recently established a collaboration between Bannu University and the University of Tuebingen. Here we report our first results of exome sequencing of four families with presumed monogenetic epilepsy and Mendelian inheritance pattern. In Family #201, we identified distinct disease-causing variants. One had a homozygous pathogenic missense variant in TSEN54 (c.919G > T, p.(Ala307Ser)), linked to Pontocerebellar Hypoplasia Type 2A. The second individual had a homozygous class IV missense variant in MOCS2 (c.226G > A, p.(Gly76Arg)) which is associated with Molybdenum cofactor deficiency. In family EP02, one affected individual carried a heterozygous class III variant in OPHN1 (c.1490G > A, p.(Arg497Gln)), related to syndromic X-linked intellectual disability with epilepsy. Our small study demonstrates the promise of next-generation sequencing in genetic epilepsies among the Pashtun population. Diagnostic next-generation sequencing should be established in Pakistan as soon as possible, and if not feasible, genetic research projects may pioneer this path.

The ribbon synapses of cochlear inner hair cells (IHCs) employ efficient vesicle resupply to enable fast and sustained release rates. However, the molecular mechanisms of these physiological activities remain unelucidated. Previous studies showed that the RAB-specific GTPase-activating protein TBC1D24 controls the endosomal trafficking of the synaptic vesicles (SVs) in Drosophila and mammalian neurons, and mutations in TBC1D24 may lead to non-syndromic hearing loss or hearing loss associated with the DOORS syndrome in humans. In this study, we generated a knock-in mouse model for the p. S178L mutation in TBC1D24, which leads to autosomal dominant non-syndromic hearing loss (DFNA65). The p.S178L mutant mice show mild hearing loss and progressively declined wave I amplitude of the auditory brainstem responses. Despite the normal gross and cellular morphology of the cochlea, transmission electron microscopy reveals accumulation of endosome-like vacuoles and a lower-than-normal number of SVs directly associated with the ribbons in the IHCs. Consistently, patch clamp of the IHCs shows reduced exocytosis under prolonged stimulus. ARF6, a TBC1D24-interacting protein also involved in endosomal membrane trafficking, was underexpressed in the cochleae of the mutant mouse and has weakened in vitro interaction with the p.S178L mutant TBC1D24. Our results suggest an important role of TBC1D24 in maintaining endosomal-mediated vesicle recycling and sustained exocytosis of hair cell ribbon synapses.

The exponential growth of next-generation sequencing (NGS) data requires innovative bioinformatics approaches to unravel the genetic underpinnings of diseases. Hemiplegic migraine (HM), a debilitating neurological disorder with a genetic basis, is one such condition that warrants further investigation. Notably, the genetic heterogeneity of HM is underscored by the fact that approximately two-thirds of patients lack pathogenic variants in the known causal ion channel genes. In this context, we have developed PathVar, a novel bioinformatics algorithm that harnesses publicly available tools and software for pathogenic variant discovery in NGS data. PathVar integrates a suite of tools, including HaplotypeCaller from the Genome Analysis Toolkit (GATK) for variant calling, Variant Effect Predictor (VEP) and ANNOVAR for variant annotation, and TAPES for assigning the American College of Medical Genetics and Genomics (ACMG) pathogenicity labels. Applying PathVar to whole exome sequencing data from 184 HM patients, we detected 648 variants that are probably pathogenic in multiple patients. Moreover, we have identified several candidate genes for HM, many of which cluster around the Rho GTPases pathway. Future research can leverage PathVar to generate high quality, candidate pathogenic variants, which may enhance our understanding of HM and other complex diseases.

The patient had clinical suspicion of THES. Complex genetic analyzes using WES, WGS were performed without success in the diagnosis. Further molecular analyzes using RNA and protein was necessary to reach the final correct THES diagnosis.

SGSM proteins are small modulator proteins interacting with proteins in the RAS signaling pathway. Studies with mouse and human tissues indicated that SGSM genes were highly expressed in the brain and could be expressed at different levels at different stages of development in fetal and adult brain tissue. It was first reported by Birnbaum et al. that the SGSM3 gene might be associated with a Mendelian inherited disease in families of Ashkenazi Jews with clinical manifestations of intellectual disability (ID). In this study, a novel homozygous stop-gain (NM_015705.6: c.1576C>T: p.(Arg526Ter)) variation was detected in the SGSM3 gene in two siblings with short stature and ID findings. The report of two cases with bi-allelic LOF variants in the SGSM3 gene from different populations with similar clinical manifestations strengthens the potential of this gene as a candidate gene for the nonsyndromic ID phenotype. Functional studies are required to investigate the signaling pathways affected by SGSM3 gene variations to produce the ID phenotype and their effect on the functioning of neurons.

Plasma membrane calcium ATPases (PMCAs) encoded by ATP2B genes have been implicated in Mendelian diseases with ataxia, dystonia, and intellectual disability. Work to date has shown that ATP2B2 (encoding PMCA2) is required for synaptic function and Purkinje-cell integrity in the cerebellum. A recent case series has linked ATP2B2 to a novel entity, characterized by neurodevelopmental and movement phenotypes, in only seven individuals. We called for collaboration to collect five unpublished families affected by the new rare ATP2B2-related condition. Exome-/genome sequencing-identified genotypes included four likely pathogenic/pathogenic heterozygous de novo missense variants and one dominantly inherited end-truncating frameshift allele. The six affected individuals shared features with the described patients including developmental delay, cognitive disturbances, epilepsy, autistic traits, and motor disorders. Striking cerebellar atrophy was observed in one affected individual. In association with hearing loss and movement abnormalities, we report a recurrent p.(Glu457Lys) substitution, previously documented in a neurologically impaired ATP2B2 mouse mutant. Our study further delineates the mutational spectrum and presentation of a human syndrome caused by ATP2B2 variants, confirming the importance of PMCA2 in neurotypical and cerebellar development.