A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.

Background: Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early-onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non-progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified.

Methods: Following the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR-based Sanger sequencing.

Results: A novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand-binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP-binding domain.

Conclusion: Our findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype-phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.