Tiyasha De, Pooja Sharma, Bharathram Upilli, A Vivekanand, Shreya Bari, Akhilesh Kumar Sonakar, Achal Kumar Srivastava, Mohammed Faruq
{"title":"印度的脊髓小脑共济失调 27B 型 (SCA27B):一项大型队列研究揭示了其古老的起源。","authors":"Tiyasha De, Pooja Sharma, Bharathram Upilli, A Vivekanand, Shreya Bari, Akhilesh Kumar Sonakar, Achal Kumar Srivastava, Mohammed Faruq","doi":"10.1007/s10048-024-00770-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"393-403"},"PeriodicalIF":1.6000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Spinocerebellar ataxia type 27B (SCA27B) in India: insights from a large cohort study suggest ancient origin.\",\"authors\":\"Tiyasha De, Pooja Sharma, Bharathram Upilli, A Vivekanand, Shreya Bari, Akhilesh Kumar Sonakar, Achal Kumar Srivastava, Mohammed Faruq\",\"doi\":\"10.1007/s10048-024-00770-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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.</p>\",\"PeriodicalId\":56106,\"journal\":{\"name\":\"Neurogenetics\",\"volume\":\" \",\"pages\":\"393-403\"},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurogenetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10048-024-00770-y\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurogenetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10048-024-00770-y","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/8 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Spinocerebellar ataxia type 27B (SCA27B) in India: insights from a large cohort study suggest 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). 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.
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 ~ 1100 generations (~ 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.
期刊介绍:
Neurogenetics publishes findings that contribute to a better understanding of the genetic basis of normal and abnormal function of the nervous system. Neurogenetic disorders are the main focus of the journal. Neurogenetics therefore includes findings in humans and other organisms that help understand neurological disease mechanisms and publishes papers from many different fields such as biophysics, cell biology, human genetics, neuroanatomy, neurochemistry, neurology, neuropathology, neurosurgery and psychiatry.
All papers submitted to Neurogenetics should be of sufficient immediate importance to justify urgent publication. They should present new scientific results. Data merely confirming previously published findings are not acceptable.