Further phenotypical delineation of DLG3-related neurodevelopmental disorders

SAP102, a member of the membrane-associated guanylate kinase proteins family, is a scaffolding protein encoded by the DLG3 gene whose hemizygous variants with loss-of-function effect are associated with X-linked Intellectual developmental disorder 90. We gathered international data from 17 new individuals with 16 different DLG3 variants (10 with pathogenic loss-of-function and 6 variants of uncertain significance), and reviewed genotypic and phenotypic data from 37 previously published families with 34 different variants. Using family segregation, frequency in publication databases, protein structure modelling and in silico prediction scores, we reclassified six missense variants (five from the literature and one common to our cohort and the literature) as likely benign. Among the individuals newly reported with likely pathogenic or pathogenic DLG3 variants, intellectual disability was more frequently associated with morphological features than in the literature, leading to a proposed extension of the associated X-linked intellectual developmental disorder 90 to a more syndromic neurodevelopmental disorder. In conclusion, we provide here an international clinical series of novel individuals with DLG3 variants in order to better define the clinical and molecular spectrum associated with this condition, and a review of the literature.