Objective: To establish clinical significance of novel recessive ataxia mutations by phenotype-genotype correlation and screening of mutations in second cohort of recessive ataxia patients and healthy controls.

Background: Autosomal recessive heareditary cerebellar ataxia(AR-HCA) are rare and clinically and genetically heterogeneous (>30 loci) disorders. Next generation sequencing capture huge number of variations per patient, but to establish clinical or pathologic consequence of a variation, requires a systematic approach to set clinical utility. From our earlier study, we have identified novel/known mutation in recessive ataxia genes by NGS. Here, we describe the analytical and clinical validation of the identified variations.

Methods: For the 13 identified mutations (three HGMD reported and 10 novel variation), clinical and analytical validation was conducted by clinical correlation, family based segregation followed by Sequenom genotyping based screening of variations in 84 unrelated recessive ataxia cases and 257 healthy controls. All patients were clinically evaluated by the neurologist and biochemical and neuroimaging data were also collected.

Results: All candidate variation were found absent in 257 healthy control(except 1 heterozygous variation of SETX). We have also not observed these variations in a set of unrelated 84 recessive ataxia patients. Clinically, five SETX mutation carriers exhibited cerebellar ataxia, sensorymotor axonal neuropathy, areflexia and cerebellar atrophy. Saccadic intrusion, extrapyramidal features, head tremors, and pes cavus were observed variably. Mutation carrier of SACS, showed cerebellar ataxia/spastic gait, hyperreflexia, pes cavus, hammer toe and saccadic intrusion. We found missense CHet mutation in GRID2 (SCAR18 gene) in a family where proband and his sibling manifested Tremor/ataxia syndrome from the age of 18 years. Brain MRI showed cerebellar atrophy in GRID2 mutation carrier. Mutation carrier of ATP7B patient did not manifested deranged copper level in blood. All variation segregated in the respective families with affected only.

Conclusions: The clinical phenotypes of identified novel mutation in our study majorly conform to the reported phenotype of each genetic subtype(AOA2, ARSACS and SCAR18). Genetic workup for ARHCA requires extensive molecular screening of each candidate gene beyond reported mutations in HGMD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-analytical-validation-of-novel-autosomal-recessive-ataxia-mutations-identified-from-whole-exome-sequencing/