OPHN1-related neurodevelopmental disorders: clinical and genetic findings with novel variants

Pathogenic variants in the OPHN1 gene are associated with X-linked intellectual developmental disorder, Billuart type (OMIM #300486), characterized by intellectual disability, distinctive facial features, cerebellar abnormalities, ventriculomegaly, epilepsy, and variable neuropsychiatric manifestations. In this study, four male individuals from four unrelated families presenting with intellectual disability and developmental delay were evaluated. Comprehensive clinical, neuroimaging, and molecular genetic data were collected. Genetic analyses were performed using whole-exome or clinical exome sequencing. Hemizygous OPHN1 variants were identified in all individuals. Two variants, a nonsense variant, c.226del (p.Leu76Ter), and a frameshift variant, c.226_227del (p.Leu76AspfsTer2), were predicted to introduce premature termination codons resulting in loss of protein function and were classified as pathogenic or likely pathogenic. Additionally, two intronic splice-site variants (c.1527-3 C > G and c.2158 + 5G > A) were classified as variants of uncertain significance; however, in silico analyses strongly supported their potential to disrupt normal splicing. The clinical features observed in the affected individuals, including developmental delay, intellectual disability of variable severity, characteristic facial features, and cerebellar and ventricular abnormalities, were consistent with previously reported OPHN1-associated phenotypes. Neuropsychiatric features, including autism spectrum disorder and hyperactivity, were also observed, highlighting phenotypic variability. This study reports the first OPHN1-related cases from Türkiye and expands the molecular and phenotypic spectrum of OPHN1-associated neurodevelopmental disorders by identifying three novel variants. Our findings support the pathogenic relevance of both loss-of-function and splice-site variants and contribute to improved genotype-phenotype correlation and diagnostic evaluation.