Expanding the spectrum of ATP8A2 mutations: a new splicing variant and systematic review of CAMRQ4 syndrome.

Background: Cerebellar ataxia, mental retardation, and disequilibrium syndrome type 4 (CAMRQ4) is a rare autosomal recessive neurological disorder caused by biallelic variants in the ATP8A2 gene. It is characterized by severe psychomotor impairment, hypotonia or spasticity, and intellectual disability. Despite increasing case reports, the full phenotypic spectrum remain incompletely defined.

Methods: We report the case of a 7-year-old girl born to consanguineous parents, presenting with severe psychomotor delay, quadriplegia, and craniofacial dysmorphisms. Whole exome sequencing identified a novel splicing variant in ATP8A2 (NM_016529.6:c.1580-3C > G). In silico tools predicted a disruption of the canonical splice acceptor site. To confirm the splicing effect, RNA was extracted from peripheral blood, followed by cDNA synthesis and PCR amplification of the region flanking the variant. Products were analyzed via gel electrophoresis.

Results: Experimental validation revealed skipping of exon 18, confirming a significant impact on splicing and supporting the reclassification of the variant as "likely pathogenic" based on ACMG criteria (PM2, PP3, and now PS3). Additionally, a systematic literature review of published CAMRQ4 cases was conducted to delineate the clinical heterogeneity associated with ATP8A2 variants.

Conclusions: This case expands the mutational spectrum of ATP8A2 and provides strong evidence for the pathogenicity of a novel splicing variant. Our findings emphasize the clinical and genetic heterogeneity of CAMRQ4 and highlight the critical role of functional RNA studies in variant interpretation. Comprehensive genotype-phenotype correlation through systematic review enhances our understanding of ATP8A2-related disorders.