Scholarlink

<p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapies, emphasizing the need for deeper understanding of disease pathogenesis. While more than 40 ALS-associated genes have been identified, their contribution varies significantly across populations and the data from the Indian population remains scarce. We aimed to comprehensively characterize the spectrum of coding DNA variations in ALS-associated genes and identify novel genetic contributors in an Indian cohort. Whole-exome sequencing on 761 ALS patients and 917 in-house healthy controls and repeat-primed PCR for expansions (<i>C9orf72</i>, <i>ATXN2</i>, <i>NOTCH2NLC</i>, <i>NOP56</i>) were performed. Variants were classified using ACMG guidelines, and rare variant association testing was conducted. Overall diagnostic yield was 15.90%, with pathogenic/likely pathogenic variants. Familial ALS showed higher diagnostic yield (36.95%) than sporadic ALS (12.96%). <i>SOD1</i> dominated familial cases (53.85%), while <i>OPTN</i>, <i>SOD1</i> and <i>FIG4</i> were prevalent in sporadic cases. Homozygous <i>SOD1</i> variants in six patients correlated with juvenile/young onset (&lt; 30 years). <i>C9orf72</i> expansions (4%) and <i>ATXN2</i> repeats (1.7%) were identified at frequencies comparable with Asian cohorts. Rare variant analysis identified <i>JAK2</i> as a novel genome-wide significant signal (FDR = 3.5 × 10<sup>−5</sup>). This first large-scale genomic survey of Indian ALS patients showed <i>SOD1</i> being the predominant cause of fALS, while <i>OPTN</i>, <i>FIG4</i>, and other genes drive disease amidst low <i>C9orf72</i> frequency. The novel <i>JAK2</i> association suggests a potential neuroinflammatory mechanism, highlighting the importance of studying diverse populations to uncover distinct genetic etiologies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis

  • 期刊论文

  • 发表日期：

    2026年7月1日

查看全文
  • Ananthapadmanabha Kotambail,
  • Gautham Arunachal,
  • Muddasu Suhasini Keerthipriya,
  • R. Mahima,
  • Ramya Sukrutha,
  • M. B. Ramyashree,
  • Madhusudhan Deekshitha,
  • Bhoomika M. Rao,
  • Purbasha Biswas,
  • Kiran Polavarapu,
  • Veeramani Preethish-Kumar,
  • Pradeep Reddy,
  • Olivia Gray,
  • Kaja A. Wasik,
  • Anne-Katrin Emde,
  • Sanjana Angadi,
  • Bhaswar Bhattacharya,
  • Marsha Zacharia,
  • K. V. Jeevitha,
  • Koneti Deepak Kumar,
  • Naveen H. Masaraddi,
  • Saraswati Nashi,
  • G. K. Chetan,
  • Seena Vengalil,
  • Atchayaram Nalini

摘要

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapies, emphasizing the need for deeper understanding of disease pathogenesis. While more than 40 ALS-associated genes have been identified, their contribution varies significantly across populations and the data from the Indian population remains scarce. We aimed to comprehensively characterize the spectrum of coding DNA variations in ALS-associated genes and identify novel genetic contributors in an Indian cohort. Whole-exome sequencing on 761 ALS patients and 917 in-house healthy controls and repeat-primed PCR for expansions (C9orf72, ATXN2, NOTCH2NLC, NOP56) were performed. Variants were classified using ACMG guidelines, and rare variant association testing was conducted. Overall diagnostic yield was 15.90%, with pathogenic/likely pathogenic variants. Familial ALS showed higher diagnostic yield (36.95%) than sporadic ALS (12.96%). SOD1 dominated familial cases (53.85%), while OPTN, SOD1 and FIG4 were prevalent in sporadic cases. Homozygous SOD1 variants in six patients correlated with juvenile/young onset (< 30 years). C9orf72 expansions (4%) and ATXN2 repeats (1.7%) were identified at frequencies comparable with Asian cohorts. Rare variant analysis identified JAK2 as a novel genome-wide significant signal (FDR = 3.5 × 10−5). This first large-scale genomic survey of Indian ALS patients showed SOD1 being the predominant cause of fALS, while OPTN, FIG4, and other genes drive disease amidst low C9orf72 frequency. The novel JAK2 association suggests a potential neuroinflammatory mechanism, highlighting the importance of studying diverse populations to uncover distinct genetic etiologies.