Objective: Comparison of two next generation platform to screen ARCA patients in Indian population

Background: India is deficient with the molecular screening of the ARCAs. Only few case reports with genetic analysis have been reported from Indian patients. Friedreich’s ataxia (FA) is the most common genetically described ARCA subtype in India. More than 1400 mutations have been reported from three major forms of ARCAs (ATM, SETX and SACS), which demonstrates screening of such genes is not straightforward, hence, systematic exploration of genetic causality ataxias in India. We utilize the power of WES in combination with targeted gene sequencing to dissect the uncharacterized autosomal recessive and early onset (<25 years) hereditary ataxia patients.

Method: All selected patients were screened negative for FRDA, SCA1, 2, 3 and 12 during mandatory screening procedure at our centre. All lab work was carried out at CSIR-IGIB laboratory, New Delhi. Patients with early onset ataxia (n=98) were subjected for Whole exome sequencing (n=16) and targeted gene panel sequencing (n=82). Frequencies of identified variation were checked in 257 ethnically matched healthy controls and in their respective family members (n=43). For four families WES was done in family based design.

Results: Targeted gene analysis (41 genes) of known candidate genes allowed us to identify 24 pathogenic/likely-pathogenic rare and novel variations in 21 patients. Disease variants in nine patients were identified through WES (56%) and in 12 patients variations were identified from targeted gene panel sequencing. By initial targeted gene analysis mutations in SACS (n=7), SETX (n=6), ATM (n=2), TTPA (n=2) and one each for GRID2, ANO10, SYNE1 and CYP27A1. By adopting family based design we could further identify likely disease variants in rare RARS2 and FA2H loci.

Conclusion: Our extensive experimental design, unbiased variant prioritization and pathogenicity supported by big data mining for genetic mutation testing serve an adapted approach for rapid and cost effective screening of clinically relevant variation. Our study suggests need of next generation sequencing in ARCA screening. In the population like India, where genetic/mutation spectrum is not well known, the targeted gene sequencing should be the first preference. Uncharacterized cases may be further considered for family based design of WES.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/need-of-next-generation-sequencing-technology-to-de-convolute-autosomal-recessive-cerebellar-ataxias-in-india/