Reevaluation of the Impact of the Novel Likely Pathogenic Variant c.1286_1288delAGA in the ATP8A2 Gene: A 7‐Year Follow‐Up With Clinical, Genetic, and ACMG Insights in an Iranian Family

TL;DR

This study reports a 7-year follow-up of a male with CAMRQ4 syndrome caused by a genetic variant in ATP8A2, confirming its role in the disorder and highlighting the importance of genetic testing.

Contribution

The study identifies a novel likely pathogenic in-frame deletion variant in the ATP8A2 gene associated with CAMRQ4 syndrome.

Findings

A homozygous in-frame deletion variant (c.1286_1288delAGA) in ATP8A2 was confirmed to be pathogenic through segregation analysis.

The study expands the known mutational spectrum of ATP8A2-related CAMRQ syndrome.

Clinical and genetic data support the importance of comprehensive genetic testing for rare neurological disorders.

Abstract

Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare neurodevelopmental disorder characterized by non‐progressive cerebellar ataxia, intellectual disability, and cerebellar atrophy. Despite its rarity, CAMRQ syndrome poses significant challenges due to its heterogeneous genetic etiology and complex clinical presentation. This study details the evolving clinical phenotype over 7 years in a male with CAMRQ4 syndrome caused by an in‐frame deletion variant in ATP8A2 gene.

A detailed clinical evaluation was performed, accompanied by tests and imaging studies. Clinical and genetic investigations, including segregation analysis, were carried out to confirm the pathogenicity of the identified variant. The evolving clinical phenotype of the patient, including developmental delay, cerebellar ataxia, and hand‐foot crawling, was thoroughly investigated.

A 10‐year‐old male patient with CAMRQ syndrome exhibited typical clinical manifestations including impaired motor coordination, cognitive impairment, and balance disturbances. Genetic analysis revealed a homozygous in‐frame deletion variant (c.1286_1288delAGA) in the ATP8A2 gene, implicating ATP8A2 in the pathogenesis of CAMRQ syndrome. This variant was predicted to be likely pathogenic and deleterious, in accordance with its segregation in affected family members. Our findings expand the mutational spectrum of ATP8A2‐associated CAMRQ syndrome and underscore the importance of comprehensive genetic testing in diagnosing rare neurological disorders.

The identification of an in‐frame deletion variant in the ATP8A2 gene enhances our understanding of CAMRQ syndrome and highlights the phenotypic variability of the disorder. Our study contributes to the elucidation of CAMRQ syndrome by identifying a novel genetic variant and elucidating its clinical and genetic implications. Further research is warranted to advance our understanding of CAMRQ syndrome and to improve patient care and management strategies.

This study reports a 7‐year follow‐up of a male with CAMRQ4 syndrome caused by a homozygous in‐frame deletion (c.1286_1288delAGA) in ATP8A2. Clinical and genetic analyses confirm its pathogenicity, expanding the mutational spectrum of ATP8A2‐related CAMRQ and underscoring the importance of comprehensive genetic testing in rare neurological disorders.

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