Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)

Abstract

Background Homozygous frameshift mutation in RUBCN (KIAA0226), known to result in endolysosomal machinery defects, has previously been reported in a single Saudi family with autosomal recessive spinocerebellar ataxia (Salih ataxia, SCAR15, OMIM # 615705). The present report describes the clinical, neurophysiologic, neuroimaging, and genetic findings in a second unrelated Saudi family with two affected children harboring identical homozygous frameshift mutation in the gene. It also explores and documents an ancient founder cerebellar ataxia mutation in the Arabian Peninsula. Case presentation The present family has two affected males (aged 6.5 and 17 years) with unsteady gait apparent since learning to walk at 2.5 and 3 years, respectively. The younger patient showed gait ataxia and normal reflexes. The older patient had saccadic eye movement, dysarthria, mild upper and lower limb and gait ataxia (on tandem walking), and enhanced reflexes in the lower limbs. Cognitive abilities were mildly impaired in the younger sibling (IQ 67) and borderline in the older patient (IQ 72). Nerve conduction studies were normal in both patients. MRI was normal at 2.5 years in the younger sibling. Brain MRI showed normal cerebellar volume and folia in the older sibling at the age of 6 years, and revealed minimal superior vermian atrophy at the age of 16 years. Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers. Autozygosity mapping focused on smallest haplotype on chromosome 3 and mutation age analysis revealed the mutation occurred approximately 1550 years ago spanning about 62 generations. Conclusions Our findings validate the slowly progressive phenotype of Salih ataxia (SCAR15, OMIM # 615705) by an additional family. Haplotype sharing attests to a common founder, an ancient RUBCN mutation in the Arab population.

Hematological findings associated with tubulin‐folding cofactors D‐related encephalopathy: Expanding the phenotype

“…We performed filtering steps on the WES as described previously 12,13,15‐17 . The analysis yielded a single most plausible candidate, a homozygous missense variant in TBCD (NM_005993.5: c.1712A > G, p.K571R) in family A. Sanger sequencing confirmed complete segregation of the variant within the family (Figure 1(A)).…”

“…The sequencing was performed on the Ion Proton™ System (Life Technologies), using Ion PI™ Sequencing 200 Kit v3 with the Ion PI™ Chip Kit v2 (Life Technologies). WES data was filtered and the candidate variants were confirmed by Sanger Sequencing 12,13 . Variants were tested for potential pathogenicity using various prediction algorithms tools 14 …”

Genetics of ataxia telangiectasia in a highly consanguineous population

“…Hence, we have taken into account the approximate mean length of the haplotype surrounding the mutation site. We then estimated the age of the mutation, as described earlier (Al-Hassnan et al, 2015;AlMuhaizea et al, 2020;Seidahmed et al, 2020).…”

“…This is due to the high rate of consanguineous marriages, large family size, and tribal nature, which directly shape the landscape of genetic diseases in the country. The prevalence of autosomal recessive diseases in Saudi Arabia is relatively high, and several novel founder mutations have been identified in this highly inbred population (Al-Hassnan et al, 2015;AlMuhaizea et al, 2020;Seidahmed et al, 2020). Hereditary ataxias (HAs) are clinically and genetically heterogeneous conditions marked by motor incoordination.…”

Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

“…Overall, in addition to the dominant negative effect of the ELOVL4 mutant on SCA34[178, 179], abnormal VLCFAs may be the main contributor to SCA34 and SCA38 through various mechanisms, in which LD dyshomeostasis may play a key role. An ancient mutation that causes the deletion of Rubicon FYVE-like domain is linked to autosomal recessive spinocerebellar ataxia (SCAR15) [190,191]. Mechanistically, it was thought that mislocalization of Rubicon underlies the pathogenesis [192].…”