背景:印度的种族多样性为研究遗传性疾病突变起源的历史提供了独特的机会。脊髓小脑共济失调27B型(SCA27B),最近发现的显性遗传性小脑疾病是由成纤维细胞生长因子14(FGF14)内含子1中的GAA重复扩增引起的.主要报道在欧洲人口中,我们旨在筛选这种突变并研究印度共济失调患者SCA27B的创始人单倍型。
方法:我们在约1400名无特征共济失调患者和亲属的大型印度队列中进行了GAA重复序列的筛查,并进行了基于长读数测序的GAA重复长度评估。还进行了基于高通量基因分型的单倍型分析。我们利用约1000个印度基因组来研究GAA风险扩展等位基因。
结果:我们报告了在未表征的印度共济失调队列中SCA27B的高频率为1.83%(n=23)。我们观察到一些双等位基因GAA扩增突变(n=5)与年轻的疾病发作。我们在连锁不平衡的74kb区域上观察到FGF14-GAA基因座侧翼的风险单倍型(AATCCGTGG)。我们进一步研究了不同地理人群中这种风险单倍型的频率。在欧洲人群中观察到风险单倍型的患病率最高(29.9%),其次是印度人(21.5%)。观察到的风险单倍型已经存在了~1100代(~22,000年),假设有相关的家谱。
结论:这项研究为SCA27B及其在印度次大陆上旧石器时代的起源提供了有价值的见解。双等位基因扩张的高发生率可能与印度人口的内婚性质有关。
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 ~ 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 ~ 1000 Indian genomes to study the GAA at-risk expansion alleles.
RESULTS: 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 ~ 1100 generations (~ 22,000 years), assuming a correlated genealogy.
CONCLUSIONS: 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.