Neurology-Genetics最新文献

Background and objectives: Our aim has been to describe a patient with a novel loss-of-function variant of the ganglioside-induced differentiation associated protein 2 (GDAP2) gene in homozygosis causing autosomal recessive cerebellar ataxia.

Methods: We studied the virtual gene panel of hereditary ataxia with onset in adulthood (version 4.15) of PanelApp by means of whole exome sequencing. The validation of the variant of interest found was performed by Sanger sequencing. A segregation study was performed on family members.

Results: The patient is a man who started at age 32 years with dysarthria soon followed by cerebellar ataxia. On evolution, spasticity, cervical dystonia, and cognitive impairment were observed. A premature stop codon variant was detected in homozygosity in exon 2 of the GDAP2 gene: c.57_59delinsACCCCAGCT (p.Trp19*). It was also detected in the patient's mother and brother, who were heterozygous, and 4 nephews on the paternal side, who were also carriers of the variant.

Discussion: This null variant in the GDAP2 gene has not been previously described in the literature associated to ataxia, neither is it present in population databases. It is considered probably pathogenic (PVS1 and PM2) and as such can be classified from this study, providing further evidence on the association of GDAP2 with hereditary cerebellar ataxia.

Background and objectives: Exome sequencing (ES) is increasingly used in the diagnostic workup of epilepsies. While its utility has been extensively demonstrated in children, its role in adults remains to be defined. In this study, we evaluate the outcomes of a holistic exome-based approach in adults with epilepsy.

Methods: We included 106 adults with epilepsy and a presumed genetic etiology between January 2015 and December 2023 at the Medical University of Vienna, Austria. Diagnostic ES, including copy number variation (CNV) and mitochondrial analyses, was performed. We report on diagnostic outcomes, phenotype expansions, and research findings. Furthermore, we compared the diagnostic outcomes with 3 comprehensive gene panels.

Results: In our cohort, the diagnostic yield was 30.2%, outperforming all 3 simulated gene panels. A developmental and epileptic encephalopathy phenotype was associated with receiving a genetic diagnosis. Overall, 27 distinct molecular etiologies were identified. Eight patients had pathogenic CNVs, and 2 had mitochondrial DNA variants. Molecular diagnoses had potential clinical implications in 8 of 32 solved cases (25%), which were eventually exerted in 5 patients (15.6%). Tailored treatment changes were successfully applied in SCN1A-related epilepsy (discontinuation of sodium channel blockers) and GLUT1 deficiency (ketogenic diet). Three patients with mitochondrial diseases were referred for preventive screening investigations after the genetic diagnosis. Our findings expand the clinical spectrum of 3 known epilepsy genes. In addition, explorative variant prioritization identified heterozygous truncating variants in CLASP1 in 2 unrelated patients with focal epilepsy, suggesting it as a candidate gene.

Discussion: Our study strongly supports the use of holistic genetic approaches, encompassing CNV and mitochondrial analyses, in adults with epilepsy. Similar to pediatric cohorts, results may inform clinical care. Moreover, we report on phenotype expansions and a candidate gene discovery.

Background and objectives: Clinical phenotype and course of individuals with 4 copies of the SMN2 gene are insufficiently described, and presymptomatic treatment remains controversial.

Methods: This is a cohort study that analyzed data from SMA patients with zero SMN1 and 4 SMN2 copies collected in the "Registre SMA France" to describe epidemiology, clinical presentation, and course.

Results: A total of 140 of 1,112 patients with SMA carried 4 SMN2 copies (16% of those with available SMN2 copy number). The median age at onset was 3.5 years (6 months-20 years), and the median follow-up was 32 years. Twelve patients (8.6%) did not walk independently (SMA2). Of them, most were able to stand or walk with support (72%). Independent walking was acquired in 91% (123 SMA3, 5 SMA4), and one-third of them lost this ability (median 16 years). Loss of ambulation was significantly earlier in children with onset before 3 years (SMA3a). There was a significant predominance of male participants in the whole cohort (63%) and in subcohorts (SMA2, 83%; SMA3, 61%; adult population, 68%). There was a significant lower risk for female participants to lose ambulation (p = 0.01). Sixty-five percent of patients used a wheelchair. Scoliosis surgery and ventilation were required in less than 15%.

Discussion: Most SMA patients with 4 SMN2 copies in the French population show an onset during childhood and a progressive course with absence or loss of ambulation before adulthood. Presymptomatic treatment seems an acceptable option to consider, although identification of individual pejorative markers of early or severe phenotypes would allow more targeted approaches. Our results and literature suggest a gender effect in this population.

Trial registration information: NCT04177134.

Background and objectives: Somatic variants in brain-related genes can cause neurodevelopmental disorders, but detailed characterizations of their clinical phenotypes, neurobehavioral profiles, and comparisons with individuals with germline variants are limited.

Methods: Using data from the Simons Searchlight natural history cohort, which uses standardized parent-report data collection methods, we identified individuals with neurodevelopmental disorders caused by pathogenic somatic variants and examined their phenotypic data. We further used results from standardized measurements of adaptive functioning, social behavior, and emotional and behavioral problems to compare individuals with somatic variants with those with germline variants.

Results: We identified 15 probands with pathogenic or likely pathogenic somatic variants in the Simons Searchlight cohort. For 8 individuals with detailed phenotype information, symptoms included developmental delay or language delay (n = 8), hypotonia (n = 5), autism spectrum disorder (n = 4), and epilepsy (n = 3). Individuals with mosaic variants showed a range of severity in their scores on standardized measurements of adaptive functioning, social behavior, and emotional and behavioral problems. In particular, some individuals with mosaic variants showed impairments that were similar in severity or more severe compared with individuals with germline variants in the same gene.

Discussion: This study improves our understanding of the clinical phenotypes and neuropsychological profiles of individuals with mosaic pathogenic variants in neurodevelopmental disorders.

Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.

Background and objectives: Investigation into different allelic variants may yield new associative genes to predict late-onset Alzheimer disease (LOAD). Variable number tandem repeats (VNTRs) are important polymorphic components of the genome; however, they have been previously overlooked because of their complex genotyping. New software can now determine differing lengths of VNTRs; however, this has not been tested in a large case-control population.

Methods: We used VNTRseek to genotype over 200,000 tandem repeats in 9,501 cases and controls from the Alzheimer's Disease Sequencing Project. We first identified limiting factors of this analysis and then examined the association of VNTRs with AD diagnosis in a subset of non-Hispanic White participants.

Results: We found that VNTRs were highly associated with areas of the genome with a high number of previously identified variants. From our case-control analysis, we identified 9 VNTRs with a repeat allele length associated with LOAD including VNTRs on DSC3, NR2E3, CCNY, PKP4, GRAP, and MAP6.

Discussion: We were able to show the feasibility of this new type of analysis in large-scale whole-genome sequencing data and identify promising VNTRs that are associated with LOAD.