Whole-exome sequencing identifies rare genetic variants in Egyptian patients with hypertrophic cardiomyopathy: a pilot study.

Dilated Cardiomyopathy in a Kurdish–Arab Cohort Using Targeted Next-Generation Sequencing

Background: Pediatric dilated cardiomyopathy (DCM) is a genetically heterogeneous disorder with limited population-specific genetic data in Middle Eastern cohorts. Methods: Twenty-three pediatric DCM patients from a predominantly Kurdish–Arab consanguineous population underwent comprehensive clinical evaluation and targeted next-generation sequencing (NGS) using a 152-gene cardiomyopathy panel. Variants were classified according to ACMG/AMP guidelines. Results: Targeted NGS identified 163 rare variants; 24 (14.7%) were pathogenic/likely pathogenic (P/LP), 76 (46.6%) were variants of uncertain significance (VUS), and 63 (38.7%) were benign/likely benign. The overall diagnostic yield was 78.3% (18/23). The SCN5A c.1921delC (p.Gln641ArgfsTer3) frameshift variant was the most frequently detected P/LP variant, present in 69.6% of patients. No significant genotype–phenotype correlations were observed for SCN5A c.1921delC regarding age of onset, left ventricular ejection fraction, or valvular/structural abnormalities. Parental consanguinity was high (66.7%), and disease onset occurred early (mean 2.0 ± 3.27 years). Conclusions: This is the first genetic evaluation of a pediatric cohort with DCM from a mixed Kurdish–Arab population. A high diagnostic yield of DCM was found, particularly in consanguineous families, including an SCN5A recurrent variant. The study highlights the utility of targeted NGS in a consanguineous population. Further related studies are required in this region.

Whole exome sequencing of an Algerian Parkinson’s disease cohort: an exploratory study identifying rare variants in putative candidate genes

Parkinson’s disease (PD), a complex neurodegenerative disorder, is increasingly prevalent, with a strong genetic component. While environmental factors contribute, the exact cause remains elusive. Understanding PD’s genetic basis is vital for advancing research and treatment. This study seeks to investigate the genetic diversity of Parkinson’s disease in the Algerian population using whole exome sequencing (WES), with the goal of identifying rare variants across genes potentially associated with the disease. Whole exome sequencing (WES) was performed on a cohort of 19 Algerian patients with clinically confirmed Parkinson’s disease, including 8 patients with a positive family history. Variant annotation and functional effect prediction were performed using SnpEff, in conjunction with multiple reference genomic databases. Variant calling results were stored in Variant Call Format (VCF). Variants were classified according to their minor allele frequency (MAF): rare variants were defined as those with a MAF between 0.1% and 1%, while novel variants were defined as those with a MAF ≤ 0.1% or absent from all queried reference databases. Whole exome sequencing analysis identified 73 variants distributed across 22 genes in 19 Algerian patients with Parkinson’s disease. Following prioritization, nine variants were detected across six candidate genes (DDOST, AUP1, SNORD66, TRPM7, ORC6, and GLUD2), whose association with Parkinson’s disease had not been previously reported in North African populations. These genes are involved in several cellular functions, including protein homeostasis, DNA repair, cellular metabolism, and oxidative stress response. Among them, GLUD2 emerges as a particularly compelling candidate requiring functional validation for future investigations. This preliminary study highlights the genetic diversity of Parkinson’s disease in the Algerian population and underscores the value of whole exome sequencing for the identification of rare variants in underrepresented populations. The findings suggest potential novel research avenues that may contribute to expanding knowledge of the genetic architecture of the disease. Replication studies and functional validation will be required to confirm the biological and clinical relevance of the identified variants.

Rare genetic variation in adults with surgically treated temporal lobe epilepsy: An exome sequencing study

Abstract Objective To determine the frequency of monogenic variants and pathogenic copy number variants (CNVs) in adults with surgically treated temporal lobe epilepsy (TLE). Methods We performed exome sequencing (ES), including CNV analysis, in 45 adults with TLE who had previously undergone epilepsy surgery. A diagnostic exome‐wide analysis was conducted to identify (likely) pathogenic variants related to epilepsy. In an exploratory approach, we screened a curated list of 45 common epilepsy genes for rare deleterious variants based on AlphaMissense and REVEL in silico predictions. Results No highly penetrant monogenic variants were identified in this cohort. Pathogenic CNVs were detected in two individuals, corresponding to 4.4% of the cohort: a 16p13.11 deletion in a surgery responder and a 22q11.2 duplication in a surgery nonresponder. Both CNVs are characterized by reduced penetrance and broad phenotypic variability. Moreover, we identified two predicted deleterious missense variants in the epilepsy‐associated genes KCNT1 and SLC2A1, both of which were detected in surgery nonresponders. In silico analyses, including structural evidence, suggested a potential impact on protein function; however, their clinical significance remains uncertain. Significance Monogenic causes are exceedingly rare in adults with surgically treated TLE, whereas CNVs may contribute to disease susceptibility in a small subset of patients. Our findings are consistent with previous reports indicating a low diagnostic yield of presurgical genetic testing and further support a predominantly polygenic architecture of TLE. Plain Language Summary Temporal lobe epilepsy (TLE) is a common type of epilepsy in adults, and some patients undergo surgery when medications fail. It is unclear whether genetic testing can help predict surgical success. In this study, we used comprehensive genetic testing in 45 adult TLE patients who had undergone epilepsy surgery. We did not find single‐gene causes of epilepsy. Two patients had structural genetic changes, which increase epilepsy risk but show variable effects. We also identified a few rare variants in epilepsy‐related genes, but their clinical relevance remains uncertain. Overall, our results suggest that single‐gene causes are rare in adults with TLE. Genetic testing may therefore have a low diagnostic rate in this population.

Implementation of exome sequencing for rare undiagnosed diseases in LMICs: the G2MC rare diseases exome sequencing pilot project

Genetic Testing Yield for Dilated Cardiomyopathy in a Single Lithuanian Center

Background/Objectives: Dilated cardiomyopathy is a heterogeneous disorder with a substantial genetic contribution from a variety of pathogenic variants. Hereditary isolated DCM is often caused by variants in genes encoding sarcomere proteins, as well as proteins involved in desmosomes or other cardiac cell functions. Identifying genetic causes improves our understanding of DCM pathophysiology, facilitates prognostic assessment, and enables more personalized disease management. Methods: We retrospectively analyzed genetic data from adult patients with a clinical diagnosis of isolated DCM evaluated at a Lithuanian tertiary university hospital between 2019 and 2024. All patients were tested with a next-generation sequencing cardiovascular gene panel. Results: We gathered 169 patients and initially reached a 16.0% (n = 27) genetic testing diagnostic yield. We performed all genetic variant reanalyses with the most current classification guidelines, and we found an additional eight positive cases. Our final diagnostic yield was 20.7% (n = 35). TTN was the most frequently affected gene (n = 30), whereas variants in BAG3 (n = 2), DSP (n = 1), LMNA (n = 1), and FLNC (n = 1) were rare. In total, 15 variants were novel—not described in the literature or databases. We did not observe significant clinical differences between patients with pathogenic variants and those without pathogenic variants. We expected a different clinical course with variants in genes like BAG3 or LMNA, but there were only a few cases. Conclusions: Genetic testing remains an important tool for confirming complex DCM cases and allows earlier disease management for relatives at risk.

From targeted SCN1A analysis to whole exome sequencing: clinical utility and novel genetic findings in a Hungarian paediatric epilepsy cohort

Epilepsy represents a highly prevalent neurological disorder with a significant genetic component, particularly implicating ion channel genes, including SCN1A. In this study, 431 individuals with heterogeneous paediatric-onset epilepsy phenotypes were assessed at the Department of Medical Genetics, University of Pécs between 2018 and 2024. Genetic investigations employed Sanger sequencing, targeted epilepsy gene panels, whole exome sequencing, and multiplex ligation-dependent probe amplification for SCN1A copy number analysis. Thirty-six pathogenic or likely pathogenic SCN1A variants were identified, including 15 variants which have not been reported previously. Furthermore, 9 novel variants were detected in 12 additional epilepsy-associated genes. Diagnostic yield was proportional to the breadth of genomic interrogation. WES analysis revealed 6 novel variants in 19 genes. These findings underscore the considerable genetic heterogeneity of epilepsy and demonstrate the clinical utility of gene panels and WES, particularly in complex phenotypes. The identification of novel variants enhances molecular understanding and facilitates more precise genotype-phenotype correlations, reinforcing the value of comprehensive genomic diagnostics in epilepsy management.