ATP6V0A2-related cutis laxa: identification of a recurrent exon 16 deletion with founder effect in southeastern Turkiye and a novel frameshift variant

Abstract

ATP6V0A2-related cutis laxa is a rare autosomal recessive disorder characterized by connective tissue abnormalities, developmental delay, and neurological features. While multiple sequence variants have been reported, exon-level deletions are rarely documented, and their clinical significance remains largely unknown. This study aims to present the clinical and molecular characteristics of a novel frameshift variant and recurrent exon 16 deletions in the ATP6V0A2 gene, to investigate a potential founder effect in southeastern Türkiye, and to contribute to the expanding genotype–phenotype correlation in ATP6V0A2-related cutis laxa. Ten cases from six unrelated families were evaluated. Exome sequencing, clinical exome sequencing, long-range polymerase chain reaction, gel electrophoresis, and haplotype analysis were performed. Variant interpretation followed ACMG and ClinGen guidelines. Clinical features were assessed through physical examination, developmental history, and neuroimaging. A novel homozygous frameshift variant (c.235del, p.Leu79Phefs*13) associated with severe neurological regression was identified in one case. Nine individuals carried a recurrent homozygous 380 bp deletion spanning exon 16 (c.1936-147_2055+113del). In our study, neurological regression—a feature rarely reported in the literature—was noted in two older patients. Haplotype analysis revealed shared homozygous regions in three cases, suggesting a founder effect. This cohort represents the largest reported series of ATP6V0A2-CL cases with exon 16 deletion to date. This study expands the genotypic and phenotypic spectrum of ATP6V0A2-CL and underscores the importance of copy number variation detection in next-generation sequencing-based diagnostics. The identification of a recurrent exon 16 deletion and shared haplotypes provides evidence for a founder effect in southeastern Türkiye and supports the implementation of population-specific screening for this variant.