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.

Keywords: Founder mutation; RUBCN; SCAR15; Salih ataxia.

Fig. 1

Genetic testing results. a Pedigree of the family showing the two affected patients (II.2 and II.3). Another sibling (II.4) is a carrier as well as both parents (I.1 and I.2). b AutoSNPa analysis shows runs of homozygosity (ROH) [shown as black blocks] between healthy individuals versus affected individuals in the family. Here, chromosome 3 is displayed (as RUBCN is located at the end of q arm). The numbers on the left are the genomic coordinates on the chromosome 3. c The ROH block containing RUBCN was taken into consideration during the whole exome sequencing (WES) filtering. Based on that, a homozygous variant, a single base deletion of cytosine in 2624th position, (NM_014687:exon18:c.2624delC:p.A875fs) indicated by a red arrow (also shown as in a red box) was detected in RUBCN (1c, arrow). d The image displays schematic drawing of the exons of the gene and encoded protein domains (arrow). The star shows the position of the variant

Fig. 2

Patient 1 (aged 2.5 years). a Sagittal T1 and (b) Coronal T2-weighted MR images of the cerebellum showing normal cerebellar volume and folia with no signs of atrophy. The vermis has normal size. The cerebellar gray and white matter are also normal

Fig. 3

Patient 2. a and b MR images at the age of 6 years (a) Sagittal T1 and (b) Coronal T2- weighted MR images of the cerebellum showing normal cerebellar volume and folia with normal vermis and no signs of atrophy. c and d MR images at the age of 16 years (c) Sagittal T1 and (d) Coronal T2-weighted MR images of the cerebellum showing minimal superior vermian atrophy. The other parts of the cerebellum show normal volume and folia with no signs of atrophy. The cerebellar gray and white matter are also normal