Identification and the origin of GAA expansion in FGF14 (Spinocerebellar Ataxia Type 27B): an insight from Indian subcontinent suggests an ancient origin

Background: The ethnic diversity of India provides a unique opportunity to study the history of the origin of mutations of genetic disorders. Spinocerebellar ataxia type 27B (SCA27B), a recently identified dominantly inherited cerebellar disorder is caused by GAA-repeat expansions in intron 1 of Fibroblast Growth Factor 14 ( FGF14 ). Being predominantly reported in European population, we aimed to screen this mutation and to study the founder haplotype of SCA27B in Indian ataxia patients. Methods : We have undertaken screening of GAA repeats in a large Indian cohort of ~1400 uncharacterized ataxia patients and kindreds and long-read sequencing based GAA repeat length assessment. High throughput genotyping based haplotype analysis was also performed. We also utilized ~1000 Indian genomes to study the GAA at-risk expansion alleles. Findings : We report a high frequency of 1.83% (n=23) of SCA27B in the uncharacterized Indian ataxia cohort. We observed several biallelic GAA expansion mutations (n=5) with younger onset of the disease. We observed a risk haplotype (AATCCGTGG) flanking FGF4-GAA locus over a 74 kb region in linkage disequilibrium. We further studied the frequency of this risk haplotype across diverse geographical population groups. The highest prevalence of the risk haplotype was observed in the European population (29.9%) followed by Indians (21.5%). The observed risk haplotype has existed through ~1400 generations (~28000 years), assuming a correlated genealogy. Interpretation: Through this study, we highlight the insights gained about SCA27B and its Caucasian origin in the Indian subcontinent. Occurrence of biallelic expansion is probably more due to endogamous nature of Indian population.