MOLECULAR BASIS OF HEREDITARY SPINOCEREBELLAR DEGENERATIONadmin
EXPLORING THE MOLECULAR BASIS OF HEREDITARY SPINOCEREBELLAR DEGENERATION IN A LARGE SUDANESE FAMILY
1Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
2Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan.
3 Faculty of Medicine, University of Khartoum, Sudan.
4Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Universités Paris VI UMR_S1127, 75013 Paris, France.
5Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, 75013 Paris, France.
6Department of Radiology, Dar Al Elaj specialized hospital, Khartoum, Sudan.
Background: Spinocerebellar neurodegenerative disorders (SCD) are known for their complex phenotypic and genetic heterogeneity forming a heterogeneous spectrum of disorders with hereditary spastic paraplegias (HSP) on one end and hereditary ataxias (HA) on the other. In clinical practice, limb spastic weakness and cerebellar ataxia are frequently found together and present the hallmark of SCD. The genetics of SCD has been a target for extensive researches in many parts of the world, yet little is known about the genetics of SCD in Sub-Saharan African population.
Methods: In this study, we recruited a large consanguineous Sudanese family with five affected siblings. Genomic DNA was extracted and screened for genetic variations using whole exome sequencing (WES). Analysis was done to identify the culprit variations using bioinformatics tools and in-silico prediction of variants pathogenicity.
Results: Clinical results showed a complex phenotype of progressive spastic-ataxia complicated with deafness. Microcephaly was detected in the two eldest patients. Analysis of WES data and variant prioritization 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 to similar neurological disease. The second variant (NM_006378.3:c.1588G>A) was in SEMA4D gene 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.
Conclusion: 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.
Presenter: Dr. Arwa Babai MBBS, MSc
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan