Novel frameshift mutation in the SACS gene causing spastic ataxia of charlevoix-saguenay in a consanguineous family from the Arabian Peninsula: A case report and review of literature

Figure 1 Family pedigree. Autosomal recessive spastic ataxia of charlevoix-saguenay affected members of the family are depicted with black target circle. Squares represent males and circles females. The proband is marked with an arrowhead. Notice the extensive consanguinity. Wt: Wild type; Mut: Mutant.

Figure 2 Brain magnetic resonance imaging images of the proband II-3. A: T2WI transversal cut of the middle pons showing hypointense linear striations, conforming to the tigroid pattern; B: T2WI sagittal images showing atrophy of the cerebellum, predominantly at the superior vermis and relative thinning of the posterior body of the corpus callosum, reduced diameter of the cervical spinal cord. Prominent sulci, fissures and extra-axial spaces, advanced to the age of the patient; C: T2WI coronal cut showing diffuse hyperintense signal involving the lateral pontine aspects merging to the middle cerebellar peduncles.

Figure 3 Flowchart representing the filtering strategy employed in the analysis of exome sequencing to reach a diagnosis in the proband II-3. UTR: Untranslated region.

Figure 4 SACS gene location and N- to C-terminal of the sacsin protein. A: Exome sequencing summary layout depicting the SACS gene location on chromosome 13 at the top and the exons coverage in green and blue. The location of the mutation on exon 10 is represented by a vertical black line. The deletion TACT mutation in the zoomed view is shown in magenta, and the reference sequence marked with a rectangle; B: N- to C-terminal of the sacsin protein, depicting a ubiquitin-like domain that binds to the proteosome, three sacsin repeat regions with known Hsp90-like chaperone function, an xeroderma pigmentosum complementation group C-binding domain that binds to the Ube3A ubiquitin protein ligase, a DnaJ domain that binds Hsp70, and a higher eukaryotes and prokaryotes nucleotide-binding domain that facilitates sacsin protein dimerization. The horizontal black l line depicts the start of the mutation, which causes loss of function of the protein due to the loss of all amino acids downstream of the line. The blue arrow shows the disrupted protein sequences and domain of sacsin protein. Each domain is demarcated by a specific sequence highlighted by the corresponding color and amino acid number given that methionine is the first amino acid at the N-terminus.

Figure 5 Sanger sequencing of control individual and the family in Figure 1A, including the proband and his parents. The rectangle depicts the 4 deleted bases in the SACS gene. The asterisks mark the base before and the base after the deletion.