Spinocerebellar ataxia type 27B (SCA27B) in India: insights from a large cohort study suggest ancient origin

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作   者：

De, Tiyasha;  Sharma, Pooja;  Upilli, Bharathram;  Vivekanand, A.;  Bari, Shreya;  Sonakar, Akhilesh Kumar;  Srivastava, Achal Kumar;  Faruq, Mohammed; 

作者机构：

All India Institute of Medical Sciences (AIIMS) New Delhi;  Council of Scientific & Industrial Research (CSIR) - India;  CSIR Inst Genom & Integrat Biol;  All India Inst Med Sci; 

关键词：

FGF14;  MATERNAL ANTICIPATION;  DNA;  GAA repeat expansion;  Age of mutation;  SCA27B;  Haplotype; 

期刊名称：

Neurogenetics

i s s n：

1364-6745

年卷期：

2024 年 25 卷 4 期

页   码：

393-403

页   码：

摘   要：

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). Predominantly reported in the European population, we aimed to screen this mutation and study the founder haplotype of SCA27B in Indian ataxia patients.Methods We have undertaken screening of GAA repeats in a large Indian cohort of similar to 1400 uncharacterised ataxia patients and kindreds and long-read sequencing-based GAA repeat length assessment. High throughput genotyping-based haplotype analysis was also performed. We utilized similar to 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 disease onset. We observed a risk haplotype (AATCCGTGG) flanking the FGF14-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 similar to 1100 generations (similar to 22,000 years), assuming a correlated genealogy.Interpretation This study provides valuable insights into SCA27B and its Upper Paleolithic origin in the Indian subcontinent. The high occurrence of biallelic expansion is probably relevant to the endogamous nature of the Indian population.