Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disease with both clinical and genetic heterogeneity. Several loss-of-function variants in the chromodomain helicase DNA-binding protein 8 (CHD8) gene have been identified in individuals with ASD and/or developmental delay/intellectual disability. These are associated with specific clinical manifestations, including overgrowth, macrocephaly, sleep disturbance, and gastrointestinal problems. Methods: We performed clinical exome sequencing in a female patient with ASD and macrocephaly. RNA analysis from peripheral blood was carried out to investigate the functional effect of the identified variants. Results: We identified a novel maternally inherited CHD8 variant (c.5390+2T>C). Transcript analysis demonstrated that this variant disrupts the canonical splice donor in intron 30, causing splicing anomalies in the CHD7-binding domain of the CHD8 protein, resulting in a truncated inactive protein. Conclusions: In conclusion, this study identified a novel splice-site variant in the CHD8 gene with experimentally confirmed pathogenic effects on RNA splicing, expanding the mutational spectrum of CHD8-related neurodevelopmental disorders. The considerable intrafamilial phenotypic variability associated with CHD8 haploinsufficiency supports the presence of reduced penetrance and highlights the influence of modifying factors on the clinical expression of CHD8-related disorders.
Falcone et al. (Sat,) studied this question.