Expanding the spectrum of autosomal dominant ATP6V1A-related disease: case report and literature review

Background: Developmental and epileptic encephalopathies (DEE) are a group of disorders often linked to de novo mutations, including those in the ATP6V1A gene. These mutations, particularly dominant gain-of-function (GOF) variants, have been associated with a spectrum of phenotypes, ranging from severe DEE and infantile spasms to milder conditions like autism spectrum disorder and language delays. Methods: We aim to expand ATP6V1A-related disease spectrum by describing a six-year-old boy who presented with a febrile seizure, mild intellectual disability (ID), language delay, acquired microcephaly, and dysmorphic features. Results: Genetic analysis revealed a novel de novo heterozygous pathogenic variant (c.82G>A, p.Val28Met) in the ATP6V1A gene. He did not develop epilepsy, and neuroimaging remained normal over five years of follow-up. Although ATP6V1A mutations have traditionally been linked to severe neurodevelopmental disorders, often with early-onset epilepsy, they may exhibit milder, non-progressive phenotypes, challenging previous assumptions about the severity of ATP6V1A-related conditions. Conclusions: This case expands the known clinical spectrum, illustrating that not all patients with ATP6V1A mutations exhibit severe neurological impairment or epilepsy and underscoring the importance of including this gene in differential diagnoses for developmental delays, especially when febrile seizures or dysmorphic features are present. Broader genotype-phenotype correlations are essential for improving predictive accuracy and guiding clinical management, especially as more cases with mild presentations are identified.