ClinVar Genomic variation as it relates to human health

In 3 sisters, born of consanguineous Saudi Arabian parents, with autosomal recessive spinocerebellar ataxia-15 (SCAR15; 615705), Assoum et al. (2010) identified a homozygous 1-bp deletion, which they described as c.2927delC in exon 19 of the KIAA0226 gene, resulting in the use of a novel reading frame that is longer than the normal C-terminal sequence (Ala943ValfsTer146). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. The mutation was not found in 622 control chromosomes. The mutation results in the loss of the highly conserved DAG binding-like motif. Assoum et al. (2013) stated that the original report by Assoum et al. (2010) incorrectly analyzed a minor isoform of KIAA0226: the correct nomenclature for this mutation in the main isoform is c.2624delC (Ala875ValfsTer146). Assoum et al. (2013) found that transfection of mutant KIAA0226 in COS-1 and HeLa cells resulted in mislocalization of the mutant protein from the late endosome and lysosomes to diffuse cytosolic distribution. The findings suggested that the mutation results in a loss of proper protein function, and that the disorder may relate to defects in endolysosomal machinery. In 2 brothers, born to first-cousin Saudi parents, with SCAR15, Seidahmed et al. (2020) identified homozygosity for the c.2624delC mutation (c.2624delC, NM_014687) in exon 18 of the RUBCN gene. The mutation, which was found by whole-exome sequencing, segregated with the disease in the family. Maddirevula et al. (2019) had previously described the mutation in the Saudi brothers (18DG0163) as c.2489delC based on NM_001145642.2. By autozygosity mapping focused on the smallest shared region of homozygosity and mutation age analysis, Seidahmed et al. (2020) determined that the mutation occurred approximately 1,550 years earlier, spanning about 62 generations. (less)