Aug 2026· European Journal of Human Genetics· 0 citations· 44 references
Medicine
TL;DR
A high prevalence of rare (mainly de novo) genetic variants in individuals with severe and sporadic DLD is revealed, and extensive molecular overlap with other neurodevelopmental disorders is demonstrated.
Abstract
A developmental language disorder (DLD) is a neurobiological condition characterized by impaired language development despite adequate linguistic input and normal intelligence. The role of monogenic causes in the pathogenesis of DLD is largely unknown and diagnostic genetic testing is rarely offered. This study assessed the diagnostic yield of genome sequencing in severe DLD and investigated the underlying genetic foundations. We designed a prospective cohort study involving trio-based genome sequencing in 25 individuals (aged 3-25 years) with severe DLD, no intellectual disability (non-verbal IQ ≥ 70), no autism spectrum disorder diagnosis and no first-degree family history of DLD or neurodevelopmental disorders. (Likely) pathogenic variants were found in nine of 25 individuals, reflecting a molecular diagnostic yield of 36%. The genetic causes were diverse and involved seven autosomal dominant disorders, one autosomal recessive disorder, and one sex chromosome aneuploidy. In seven individuals, the disease-causing variant occurred de novo. All identified (likely) pathogenic variants were located in genes or loci that have been previously implicated in neurodevelopmental disorders with variable clinical presentations. Importantly, the genetic diagnosis provided actionable insights for counselling and clinical follow-up for all nine individuals. This study reveals a high prevalence of rare (mainly de novo) genetic variants in individuals with severe and sporadic DLD, and demonstrates extensive molecular overlap with other neurodevelopmental disorders. Our results support the implementation of routine trio-based genetic testing in individuals with severe and sporadic DLD.
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.
A. Theodosiou, L. Kousoulidou, Ioannis Papaevripidou et al.· Genes· 0 citations
Clinical heterogeneity among children with NRXN1 deletions illustrates clinical heterogeneity among children with autism spectrum disorder and supports the need for larger studies to better define genotype-phenotype relationships.
Samira Said AlHousni, A. Idris, Watfa Al-Mamari et al.· Sultan Qaboos University Med...· 0 citations
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.
Emma Ehn, H. Thonberg, Inger Nennesmo et al.· Human Molecular Genetics· 0 citations
The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.
Varada Vidya Rani, Suryanarayana Reddy Kovvuri, D. Arya· Genetics and Molecular Resea...· 0 citations
Autism spectrum disorder (ASD) is genetically heterogeneous, involving rare and common variants that disrupt neurodevelopmental pathways. To explore this complexity, we performed whole-exome sequencing in children with ASD. Clinical phenotypes were systematically recorded, and severity was classified according to DSM-5 criteria. Variants were interpreted using ACMG guidelines, with recurrence analysis to identify genes shared across individuals and cohort enrichment testing against gnomAD. To examine genotype-phenotype relationships, we applied SKAT/SKAT-O across 16 phenotypes after covariate adjustment. Among 25 included individuals, pathogenic or likely pathogenic variants were found in 9, yielding a diagnostic yield of 36%. These involved genes linked to neurodevelopmental, epileptic, metabolic, and syndromic disorders. Recurrence analysis identified 586 genes present in at least two individuals, with PABPC1, GTF2I, PCLO, PKD1, and EP400 being the most frequent. SKAT/SKAT-O revealed the strongest burden associations for motor delay, aggressive behavior, mutism, anxiety, unresponsiveness to spoken voice, digestive disorder, and sleep disturbances, with limited overlap across phenotypes. Several recurrent genes also showed phenotype-specific associations. Overall, this integrative WES study provides clinically actionable diagnoses, highlights recurrent genes, and uncovers phenotype-specific signals, supporting convergent pathways with gene-level heterogeneity.
Zainab Gaouzi, Giulia Spoto, F. Polito et al.· International Journal of Mol...· 0 citations
Congenital eye malformations represent a clinically and genetically heterogeneous group of disorders. Despite advances in genetic testing, fewer than half of affected patients receive a definitive molecular diagnosis. However, obtaining a molecular diagnosis is crucial for these patients and their families. Whole genome sequencing (WGS) is now standard practice in the genetic investigation of patients, but its contribution has not been extensively evaluated in patients with ocular malformations. In this work, we performed short-read WGS in a cohort of 100 families presenting with eye developmental disorders, including microphthalmia-anophthalmia spectrum (M/A), coloboma, anterior segment dysgenesis, congenital cataracts and/or foveal hypoplasia. Prior to WGS, 47 individuals had undergone targeted next-generation sequencing (NGS) of genes panels related to ocular development, 11 had chromosomal microarray analysis (CGH-array) and 20 had a combination of both. None had received a definitive genetic diagnosis. WGS identified a (likely) pathogenic variant in eighteen patients. In addition, candidate variants of uncertain significance were detected in nine patients. Notably, fourteen of these variants would have been missed by conventional genes panels or CGH-array, underscoring the broader diagnostic scope of WGS. Our findings demonstrate that short-read WGS significantly improves diagnostic yield in patients with congenital eye malformations, including those previously undiagnosed despite NGS panel testing. These results support the integration of WGS in the genetic evaluation of ocular developmental disorders.
Bertrand Chesneau, Timotéo Cousteix, Abdelhakim Bouazzaoui et al.· European Journal of Human Ge...· 1 citation· ⚡1
