Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.

Discovery of Causative Genetic Variants in Patients with Congenital and/or Developmental Anomalies by Exome Sequencing

This study provides the first systematic, mutational-level characterization of a Cypriot Mendelian disease cohort, establishing a local baseline diagnostic yield and revealing a high proportion of novel variants that reflect the underrepresentation of Eastern Mediterranean populations in global databases.

Clinical heterogeneity and diagnostic challenges in CASK-related neurodevelopmental disorders: a longitudinal observational study

CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.

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.

GCH1 genetic variation as a prognostic factor in Parkinson disease across populations

Whole-exome sequencing reveals novel and previously reported variants in genes linked to white matter pathology in neurodevelopmental disorders.

Functional neuronal networks are essential for brain growth and development, with myelin or "white matter" playing a key role not just in neuronal transmission but also in axonal support, maintenance, and repair. Disruption of these networks through genetic variation contributes to a range of neurodevelopmental disorders, including both primary inherited white matter disorders and an ever increasing list of secondary leukodystrophies or leucoencephalopathies. Traditionally identified using neuroimaging techniques such as magnetic resonance imaging (MRI), clinico-radiological heterogeneity means MRI alone is rarely sufficient in providing a diagnosis requiring integration with genomic techniques and expert medical review. In this study, we describe an exome-first approach in a cohort of 78 consanguineous families with undiagnosed neurodevelopmental disorders in a healthcare resource-poor setting. The aim is to demonstrate that, even in the absence of MRI imaging, we have the potential to improve diagnostic accuracy and yield. We report positive findings in six families, including known variants in MLC1, AIMP1, ASPA, and DEGS1, and novel variants in XPA and POLR3B. This study highlights the effectiveness of whole-exome sequencing as a diagnostic tool for heterogeneous neurological disorders and provides additional evidence supporting gene-disease associations in conditions linked to white matter pathology.

Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project.

Whole-genome sequencing (WGS) projects for rare disease diagnosis typically yield a diagnostic rate of 25-41%, depending on the methods for patient selection and the extent of prior genetic testing. The Scottish Genomes Partnership (SGP) is a collaborative programme using genome sequencing to diagnose rare disease patients with presumed monogenic aetiology in the Scottish NHS. Within SGP, short-read sequencing (SRS) had previously achieved a diagnostic rate of 23% in affected families. To increase diagnostic yield, we applied Oxford Nanopore Technologies (ONT) long-read sequencing (LRS) to a cohort of 24 SGP families (74 individuals) that remained undiagnosed after SRS-based SNV/indel analysis. We also retrospectively reviewed SRS-derived structural variant (SV) calls to assess whether LRS results could have been detected in SRS data. After quality, rarity, panel-based and inheritance-based filtering, 392 candidate SVs were retained across de novo, homozygous recessive, compound heterozygous and X-linked inheritance models, of which 8 overlapped PanelApp diagnostic-grade "green" genes. Pathogenic or likely pathogenic de novo SVs were identified in 3 of 24 families: an AUTS2 inversion, a DLX5/6 locus inversion, and an FN1 deletion. All three SVs were independently confirmed by retrospective SRS re-analysis using SVRare. These findings demonstrate that LRS-based SV analysis, supported by orthogonal SRS re-analysis, can resolve clinically significant SVs in families who remain unsolved after standard rare disease testing.