Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), are increasingly recognized as conditions with a complex, multisystemic origin. ASD frequently co-occurs with other neurological conditions, such as epilepsy. We report a female patient, born to unrelated healthy parents, presenting with a complex clinical phenotype characterized by ASD level 1 with fluent speech, borderline intellectual functioning (BIF), coordination disorder, and epilepsy. Trio-based whole-exome sequencing (WES) revealed a de novo variant in the USP24 gene (c.3155G>T; p.Ser1052Ile), classified as likely pathogenic according to ACMG criteria (PS2, PM2, PP2, BP4). USP24 has previously been associated with Parkinson’s disease and has recently emerged as a candidate risk gene for ASD. In addition, WES detected two variants of uncertain significance (VUS), both inherited from the clinically unaffected father: c.388G>C (p.Gly130Arg) in NRXN2 and c.6395C>A (p.Ser2132Tyr) in LRP2. Although neither gene shows a fully penetrant causal relationship with the observed phenotype, both have been implicated in neurodevelopmental disorders. Array-CGH analysis did not reveal pathogenic copy number variants; however, the presence of additional genetic contributors not detectable by WES cannot be excluded. Overall, the de novo USP24 variant likely represents the primary genetic driver of the phenotype, while the potential contribution of the inherited NRXN2 and LRP2 variants remains plausible. This case underscores the complexity of the genetic architecture underlying NDDs and supports a model involving cumulative effects of multiple variants rather than a strictly multigenic interaction.
Vinci et al. (Sat,) studied this question.