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<p>Coronary artery disease (CAD) is a leading global cause of mortality, with genetic predisposition conferring a more than two-fold increased risk in individuals with a family history of premature disease. This study aimed to identify rare genetic variants underlying inherited premature CAD (PCAD) in familial cases. Fifty unrelated Iranian families with early-onset familial CAD/MI were recruited. Inclusion required at least two affected members with PCAD (≤ 45&#xa0;years in men, ≤ 55&#xa0;years in women) across generations. Whole-exome sequencing (WES) data analysis was performed using the Illumina DRAGEN Bio-IT platform for alignment and variant-calling, and Ilyome software for annotation. Sanger sequencing was used for co-segregation analysis in additional family members. The study identified novel candidate genes potentially associated with premature CAD, as well as rare variants in well-established CAD genes in familial premature CAD, in seven unrelated families. Among the potential candidates, PIKFYVE emerged as the most compelling primary candidate, supported by its established role in cardiac calcium homeostasis, platelet function, and vascular biology. Three additional genes (<i>PKP2</i>, <i>CAPN5</i>, <i>OBSCN</i>) represent secondary novel findings that warrant further investigation. These findings expand the genetic architecture of familial PCAD and highlight the value of WES in early-onset familial cases. GTEx expression data supported the biological relevance of candidate genes. Functional studies are warranted to confirm the pathogenicity of the identified variants.</p>

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Genetic contributors to premature coronary artery disease identified by whole-exome sequencing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Mahsa Tahmasebivand,
  • Kaveh Hosseini,
  • Marzieh Mohseni,
  • Ebrahim Shokouhian,
  • Sanaz Arzhangi,
  • Fatemeh Ghodratpour,
  • Saeed Sadeghian,
  • Mohammadali Boroumand,
  • Fatemeh Shokohizadeh,
  • Elham Rostami,
  • Reza Malekzadeh,
  • Hamidreza Khorram Khorshid,
  • Reza Najafipour,
  • Mohammadreza Akbari,
  • Yasser Riazalhosseini,
  • Hossein Najmabadi,
  • Mark Lathrop,
  • Kimia Kahrizi

摘要

Coronary artery disease (CAD) is a leading global cause of mortality, with genetic predisposition conferring a more than two-fold increased risk in individuals with a family history of premature disease. This study aimed to identify rare genetic variants underlying inherited premature CAD (PCAD) in familial cases. Fifty unrelated Iranian families with early-onset familial CAD/MI were recruited. Inclusion required at least two affected members with PCAD (≤ 45 years in men, ≤ 55 years in women) across generations. Whole-exome sequencing (WES) data analysis was performed using the Illumina DRAGEN Bio-IT platform for alignment and variant-calling, and Ilyome software for annotation. Sanger sequencing was used for co-segregation analysis in additional family members. The study identified novel candidate genes potentially associated with premature CAD, as well as rare variants in well-established CAD genes in familial premature CAD, in seven unrelated families. Among the potential candidates, PIKFYVE emerged as the most compelling primary candidate, supported by its established role in cardiac calcium homeostasis, platelet function, and vascular biology. Three additional genes (PKP2, CAPN5, OBSCN) represent secondary novel findings that warrant further investigation. These findings expand the genetic architecture of familial PCAD and highlight the value of WES in early-onset familial cases. GTEx expression data supported the biological relevance of candidate genes. Functional studies are warranted to confirm the pathogenicity of the identified variants.