A novel homozygous splice-site mutation in SCARB2 is associated with progressive myoclonic epilepsy with renal failure.

Progressive myoclonic epilepsy-4 with or without renal failure (EPM4) is a rare neurological autosomal recessive disorder caused by mutations in SCARB2 gene. In this study, we described clinical features and genetic causes of an Iranian family with two affected individuals whose clinical manifestations closely resembled progressive myoclonus epilepsy. Our proband was a 38-year-old male with a history of tremor, generalized seizures, action myoclonus, ataxia, and dysarthria that presumptive diagnosed as progressive myoclonus epilepsy. His older sister has the same symptoms. Whole-exome sequencing of DNA sample from the proband was performed. Candidate variant and cosegregation were confirmed by direct sequencing. Functional prediction of candidate variant was performed using appropriate prediction tools. Genetic analysis identified a homozygous splicing c.423+1 G>A variant in the SCARB2 gene of the proband and his affected sister. Segregation study identified heterozygous state in four unaffected family members (parents and two children). The variant is localized at the first nucleotide of intron 3 and was not detected among in-house healthy controls. This variant was not reported in genetic databases and predicted to potentially alter the 5' donor splice site and disease causing using online prediction tools. It was classified as a likely pathogenic variant according to ACMG standards and guidelines. This is the first report that demonstrates c.423+1 G>A variant in the SCARB2 gene segregating with the phenotype of EPM4 in a consanguineous Iranian family.