Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degeneration

Abstract Hereditary spinocerebellar degenerative disorders (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include spastic paraplegia, spastic ataxia, cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 patients from 38 unrelated Sudanese families segregating multiple forms of SCDs focusing on known human disease-associated genes. We reached the genetic diagnosis in 63% and up to 73% of the studied families when considering variants of unknown significance. Taking into account a series of Sudanese families that we previously analyzed, the combined success rate in the two series reached 52–59% (31–35/59 families). We also highlighted the genetic and clinical heterogeneity of SCDs in Sudan, as we identified no single major gene in our cohort and the potential for discovering novel SCDs genes in this population.