Diagnostic yield and copy number variants findings in 219 adult patients with developmental and epileptic encephalopathy.

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

In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history, and provide a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap.

Chromosomal Microarray Analysis in Pediatric Patients with Neurodevelopmental Disorders and Congenital Anomalies: A Two-Center Experience

Chromosomal microarray analysis (CMA) is a first-tier diagnostic tool for children with neurodevelopmental disorders and congenital anomalies; however, interpretation of variants of uncertain significance (VUS) remains challenging. This study aimed to characterize the copy number variant (CNV) spectrum in pediatric patients with congenital anomalies and/or dysmorphic features, focusing on VUS interpretation through segregation analysis and detailed phenotype–genotype correlation. We retrospectively evaluated 28 pediatric patients with abnormal CMA results referred to two tertiary genetics clinics between 2021 and 2022. Indications included neurodevelopmental delay, intellectual disability, dysmorphism, and/or congenital anomalies. CNVs were classified according to 2020 ACMG/ClinGen standards. Parental segregation analysis was performed for 15 CNVs in 13 families, with particular attention to gene disruption caused by CNV breakpoints. The cohort included 16 males and 12 females, with a mean age of 5.28±4.39 years. Thirty-four CNVs were identified, including 14 deletions and 20 duplications; seven were pathogenic/likely pathogenic and 27 were VUS. Segregation analysis identified five de novo, six maternal, and four paternal variants. A 2q22.2 gain disrupting KYNU at intron 12 was identified in a patient with VACTERL-like features. Three patients had additional karyotypic abnormalities, highlighting the complementary role of CMA. A de novo 4p16.3 duplication disrupting both HTT and ADD1 was also identified. Our findings highlight the importance of detailed phenotyping, breakpoint analysis, and segregation studies in interpreting CNVs, particularly VUS and rare intragenic disruptions. Integrating genomic findings with clinical features and inheritance patterns may improve phenotype–genotype correlation and support the identification of candidate loci.

Copy number variant analysis by exome sequencing is an effective approach to optimize diagnostic yield for developmental disorders-the DDD-Africa study.

Copy number variants (CNV) contribute significantly to the pathogenic variation associated with developmental disorders. CNV detection is often not included in standard exome sequencing (ES) analysis. Complementary methods such as chromosomal microarray are typically offered in diagnostic laboratories to diagnose pathogenic CNV. In this study, we aimed to develop an effective approach for incorporating CNV detection within our ES analysis process for the Deciphering Developmental Disorders in Africa (DDD-Africa) cohort. We analyzed ES data from 505 probands with a developmental disorder, applying a CNV detection approach that assessed data generated using the tools CANOES and XHMM. When available, parental ES data was used to assess inheritance patterns. We confirmed a diagnosis in 41/505 (8,1%) patients with 43 pathogenic CNV identified in the probands. There were 31 deletions and 12 duplications. Among the 26 probands with parental data, all identified CNV were de novo. The addition of CNV analysis to our ES analysis pipeline resulted in an 8.1% increase in diagnostic yield in the DDD-Africa cohort without additional laboratory cost. This offers a feasible approach which is likely to reduce analytical cost and is suitable for low- and middle-income countries where funding and resources for genomic medicine initiatives are limited.

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.

Whole-exome sequencing in pediatric drug-resistant epilepsy: diagnostic yield and clinical impact in a resource-limited setting

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.