Objective: The objective of this study was to identify the molecular diagnosis of a Sudanese lady presenting with pyramidal signs and symptoms using whole exome sequencing and Sanger sequencing.

Background: CCDC88C is a ubiquitously expressed protein with multiple functions including roles in cell polarity and the development of dendrites. Bi-allelic mutations in CCDC88C gene cause autosomal recessive congenital hydrocephalus (OMIM #236600). Recently, heterozygous mutations in CCDC88C gene were linked to the development of the late onset spinocerebellar ataxia type 40 (OMIM #616053).

Method: A 48 years old Sudanese female presented with walking abnormalities since early childhood. Her examination was significant for signs of pyramidal involvement in both lower limbs. We extracted DNA from the patient and four of her relatives, and performed exome sequencing on the patient’s DNA and the DNA extracted from one of her healthy siblings. To call variants, we followed GATK4 best practice guidelines, and prioritized and filtered the called variants using VarAFT software. We used Sanger sequencing to validate the culprit variant and its segregation with the disease in the family.

Results: Exome sequencing and downstream in silico analysis revealed the heterozygous NM_001080414(CCDC88C):c.1993G>A / p.Glu665Lys (rs956104232) variant as the potential cause of pure hereditary spastic paraplegia in our patient. Five prediction software indicated its deleterious effect, and with a frequency of 0.0000032, this variant was ultra-rare in gnomAD genomes database. Unlike what had been reported previously, our patient had an early age at onset. Additionally, she showed neither features of cerebellar ataxia, extra-pyramidal signs nor evidences of intellectual involvement.

Conclusion: We here extend the phenotype associated to variants in CCDC88C gene to early onset pure hereditary spastic paraplegia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/heterozygous-mutation-in-ccdc88c-gene-as-a-cause-of-early-onset-pure-hereditary-spastic-paraplegia/