Expanding the clinical spectrum of ARV1-related disease beyond classical developmental and epileptic encephalopathy

Biallelic pathogenic variants in ARV1 are classically associated with developmental and epileptic encephalopathy-38 (DEE38), a severe infantile-onset disorder characterized by drug-resistant epilepsy, profound neurodevelopmental impairment, and early mortality. However, emerging evidence suggests broader phenotypic variability. We aimed to expand the clinical and molecular spectrum of ARV1-related disease through a retrospective case series and structured literature review.

We retrospectively identified five unrelated Saudi Arabian families with biallelic pathogenic or likely pathogenic ARV1 variants confirmed by whole-exome sequencing. Clinical, neurodevelopmental, neurophysiological, neuroimaging, and multisystem findings were reviewed. A structured literature review was performed to integrate previously reported cases.

We identified marked clinical heterogeneity, including a novel ARV1 missense variant (c.214G>T; p.Asp72Tyr), which remains classified as a variant of uncertain significance according to ACMG/AMP criteria despite multiple computational predictions supporting a deleterious effect. Clinical severity ranged from severe developmental and epileptic encephalopathy with drug-resistant epilepsy and early mortality to milder static neurodevelopmental phenotypes with sustained seizure remission and long-term survival into adulthood. Families harboring the same homozygous frameshift variant exhibited markedly different clinical severity, supporting the absence of a strict genotype-phenotype correlation. Multisystem involvement included neurological, cardiac, skeletal, sensory, gastrointestinal, and genitourinary manifestations, and metabolic phenocopies contributed to diagnostic delays.

Our findings demonstrate that ARV1-related disease represents a broad multisystem clinical spectrum, with classical DEE38 representing its most severe presentation rather than its sole manifestation. Recognition of milder phenotypes, prolonged seizure remission, and marked phenotypic variability has important implications for diagnosis, prognostic counseling, and multidisciplinary long-term surveillance. Early genomic testing should be considered in patients with early-onset epilepsy and multisystem involvement, particularly in consanguineous populations.