Exome sequencing (ES) has become a primary tool for diagnosing neurodevelopmental disorders (NDDs), yet the interpretation of genetic variants in large, heterogeneous cohorts presents significant challenges that automated pipelines often fail to resolve. This study showcases the complexities and novel findings derived from a decade-long analysis of 419 Italian NDD patient-parent trios. While ES established a molecular diagnosis in 36.5% of cases (53.8% in syndromic presentations), our investigation moves beyond diagnostic yield to highlight the critical value of manual curation integrated with deep phenotyping. We demonstrate how this rigorous approach uncovers complex disease mechanisms, revealing that variants initially misclassified as missense or stop-gain are, in fact, pathogenic splicing defects confirmed by functional analysis. Furthermore, we resolve the paradox of pathogenic truncating PPM1D variants in control databases by demonstrating their somatic mosaic nature, a crucial insight for population data interpretation. Our work also refines gene-disease correlations by challenging the established role of MID2 in NDDs, providing further evidence for DSCAM as a high-confidence risk gene, and expanding the known phenotypic spectrum of disorders, such as a novel GNAI2-related syndrome lacking expected immune dysfunction. This study underscores that navigating the complexities of large NDD cohorts requires a detailed, expert-driven approach to not only enhance diagnostic yield but also to advance our fundamental understanding of rare disease genetics.
Simona Cardaropoli, Lisa Pavinato, Slavica Trajkova et al.· Human Genetics· 0 citations
Nuclear factor I (NFI) transcription factors regulate neural stem and progenitor differentiation during brain development. While NFIA, NFIB, and NFIX are linked to neurodevelopmental disorders, the role of NFIC (MIM: 600729) in human disease remains unclear. This study aimed to determine whether NFIC contributes to a neurodevelopmental syndrome, define its phenotype, and assess dosage-dependent effects. We established the first cohort of 11 individuals, including NFIC deletions and single nucleotide variants. Genotype-phenotype correlations, including critical region mapping, were performed. Murine data and bioinformatics were integrated to explore underlying pathomechanisms. We report 11 individuals with NFIC variants, including four with de novo SNVs and seven with deletions encompassing the gene, of whom nine have not been previously reported. A core phenotype of syndromic intellectual disability and macrocephaly was delineated. Opposing cranial phenotypes relative to proximal 19p13.3 duplication cases support a dosage-sensitive effect and a mirror-syndrome model. NFIC-related disorder represents a novel neurodevelopmental syndrome characterized by intellectual disability and macrocephaly, highlighting the importance of NFIC dosage supporting a mirror-syndrome model.
Nathalie Vanden Eynde, L. Hérissant, E. Landais et al.· Clinical Genetics· 0 citations
The data establish BHLHE22 as a previously unrecognized neurodevelopmental disease gene that results in a distinct syndrome characterised by abnormalities in brain development, cognition, tone and movement.
Carolyn Le, T. Kalaycı, Z. Uyguner et al.· Journal of Medical Genetics· 0 citations