Exploring the molecular basis of hereditary spinocerebellar degeneration in a large Sudanese family

Abstract

Spinocerebellar neurodegeneration (SCD) is phenotypically and genetically complex forming a heterogeneous spectrum of disorders with hereditary spastic paraplegias on one end and hereditary ataxias on the other. Genetics of SCD has been a target for extensive researches worldwide, yet little is known about SCD genetics in Sub-Saharan African population. We recruited a large consanguineous Sudanese family with five affected siblings. Extracted genomic DNA was screened for genetic variations using whole exome sequencing (WES). Analysis was done to identify the culprit variations using bioinformatics tools. Clinical results showed a complex phenotype of progressive spastic-ataxia, deafness and microcephaly. Analysis of WES data suggested two homozygous missense variants in two candidate genes (MYO15A and SEMA5D) that were not reported to be linked to similar disease before. The first variant in MYO15A gene (NM_016239.3: c.1634C>T) was reported to cause autosomal recessive hearing loss but was not reported in similar neurological disease. The second variant in SEMA4D gene (NM_006378.3:c.1588G>A) which involved in brain development but not reported to be associated with inherited neurological conditions before. Both variants were extremely rare and highly conserved. They were predicted to be highly pathogenic using bioinformatics tools. The scarcity of genetic data in the highly consanguineous Sudanese population makes whole exome sequencing a powerful and cost effective strategy to identify both known and new pathogenic variations and genes. Sanger sequencing and further functional studies are recommended to prove the association of MYO15A gene and SEMA4D gene with the complex clinical phenotype of deafness, spasticity and ataxia.