Paradigm for disease deconvolution in rare neurodegenerative disorders in Indian population: insights from studies in cerebellar ataxias

Abstract

Cerebellar ataxias are a group of rare progressive neurodegenerative disorders with an average prevalence ranges from 4.8 to 13.8 in 100,000 individuals. The inherited disorders affect multiple members of the families, or a community that is endogamous or consanguineous. Presence of more than 3000 mutations in different genes with overlapping clinical symptoms, genetic anticipation and pleiotropy, as well as incomplete penetrance and variable expressivity due to modifiers pose challenges in genotype-phenotype correlation. Development of a diagnostic algorithm could reduce the time as well as cost in clinicogenetic diagnostics and also help in reducing the economic and social burden of the disease. In a unique research collaboration spanning over 20 years, we have been able to develop a paradigm for studying cerebellar ataxias in the Indian population which would also be relevant in other rare diseases. This has involved clinical and genetic analysis of thousands of families from diverse Indian populations. The extensive resource on ataxia has led to the development of a clinicogenetic algorithm for cost-effective screening of ataxia and a unique ataxia clinic in the tertiary referral centre in All India Institute of Medical Sciences. Utilizing a population polymorphism scanning approach, we have been able to dissect the mechanisms of repeat instability and expansion in many ataxias, and also identify founders, and trace the mutational histories in the Indian population. This provides information for genetic testing of at-risk as well as protected individuals and populations. To dissect uncharacterized cases which comprises more than 50% of the cases, we have explored the potential of next-generation sequencing technologies coupled with the extensive resource of baseline data generated in-house and other public domains. We have also developed a repository of patient-derived peripheral blood mononuclear cells, lymphoblastoid cell lines and neuronal lineages (derived from iPSCs) for ascribing functionality to novel genes/mutations. Through integrating these technologies, novel genes have been identified that has broadened the diagnostic panel, increased the diagnostic yield to over 75%, helped in ascribing pathogenicity to novel mutations and enabled understanding of disease mechanisms. It has also provided a platform for testing novel molecules for amelioration of pathophysiological phenotypes. This review through a perspective on CAs suggests a generic paradigm fromdiagnostics to therapeutic interventions for rare disorders in the context of heterogeneous Indian populations.

Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

“…Efforts are being made by various groups where uncharacterized cases are explored using next generation sequencing to decipher the unknown genetic cause. [ 1 ] Intense NGS‐Clinical Exome sequencing has helped improve characterization of ataxia cases, with a yield of ≈50–60%. Further, once an extensive study has been performed, targeted next generation sequencing approach probably helps to evaluate the unsolved cases with cost‐effective and limited resources.…”

“…From the experience of various neurology clinics and research efforts, the identification of definitive genetic etiology remains in the range of (20-40%) and a larger proportion of cases remain unknown for their etiological diagnosis. [1,4] The prevalence figures remained unknown at population scale for SCAs; however it is estimated to be 2.7 in 100 000 individuals. [4] The reported incidents of each SCA subtype vary in different geographical regions and ethnic populations; however, SCA3/MJD is considered the most common subtype worldwide.…”

“…Similarly, among specific SCA subtypes, prevalence of SCA7 is higher in Scandinavia and Venezuela, SCA12 in India and SCA17 is one of the least prevalent SCA worldwide (in polyglutamine SCAs) with frequency of 0-3% of SCA families. [1,[5][6][7] In addition the SCA subtypes linked to trinucleotide repeat expansion (TRE), the SCAs (SCA5, SCA11, SCA15, etc.) caused by single nucleotide mutations (SNMs) are less frequently reported and this fact could be biased owing to the technical challenge in investigating the SNMs per gene in these rare SCAs in comparison to investigating one mutation per gene linked to TRE loci.…”