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<p>Congenital heart disease (CHD) is the most common congenital malformation, with most cases exhibiting a multifactorial etiology involving genetic and environmental factors. Congenital anomalies of the atrioventricular valve or septum (CAAVAS) and functionally univentricular heart (FUH) are complex subtypes of CHD, where disruptions in key molecular pathways are implicated. This study investigates the genetic burden contributing to these anomalies.&#xa0;This case-control study included 48 participants: 24 patients diagnosed with CAAVAS or FUH and 24 healthy controls. Whole-exome sequencing (WES) was conducted to assess genetic burden by evaluating minor allele frequencies (MAF) using gnomAD and predicting functional impact of variants with REVEL scores. A secondary filtration was performed, focusing on 349 genes associated with abnormal heart valve morphology (HP:0001654) as defined by the Human Phenotype Ontology (HPO) database, to identify pathogenic variants exclusive to the case group.&#xa0;Genetic burden risk (GBR) analysis revealed a significantly higher median number of common variants in the case group compared to controls (<i>p</i> = 0.035). Genetic analysis identified variants in genes involved in contractile cardiac and cytoskeletal proteins (MYH3, ACTC1), extracellular matrix proteins (FBN1, FREM1, HSPG2), ciliary proteins (EVC2, PKD1L1), enzymes (POLG, DNASE1L3), cell-signaling proteins (TGFB2, CCDC22) and transcription factors (NKX2-5, NONO).&#xa0;This study highlights the significant role of genetic burden and gene variants associated with congenital mitral and tricuspid valve anomalies. Our findings reinforce the strong genetic predisposition underlying these malformations, as evidenced by the increased genetic burden in affected individuals compared to controls without CHD.</p>

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Genetic Burden in Congenital Anomalies of the Mitral and Tricuspid Valves: A Case–Control Study

  • 期刊论文

  • 发表日期：

    2026年1月24日

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  • Felix-Julian Campos-Garcia,
  • Addy-Manuela Castillo-Espinola,
  • Carolina-Elizabeth Medina-Escobedo,
  • Juan C. Zenteno,
  • Julio-Cesar Lara-Riegos,
  • Juanita-Adriana Chuc-Chan,
  • Ana-Isabel Velazquez-Ibarra,
  • Paulina-Del-Carmen Cauich-Pool,
  • Eddie-Alberto Favela-Perez,
  • Pablo-Ysidro Pech-Gomez,
  • Miguel-Angel Villasis-Keever

摘要

Congenital heart disease (CHD) is the most common congenital malformation, with most cases exhibiting a multifactorial etiology involving genetic and environmental factors. Congenital anomalies of the atrioventricular valve or septum (CAAVAS) and functionally univentricular heart (FUH) are complex subtypes of CHD, where disruptions in key molecular pathways are implicated. This study investigates the genetic burden contributing to these anomalies. This case-control study included 48 participants: 24 patients diagnosed with CAAVAS or FUH and 24 healthy controls. Whole-exome sequencing (WES) was conducted to assess genetic burden by evaluating minor allele frequencies (MAF) using gnomAD and predicting functional impact of variants with REVEL scores. A secondary filtration was performed, focusing on 349 genes associated with abnormal heart valve morphology (HP:0001654) as defined by the Human Phenotype Ontology (HPO) database, to identify pathogenic variants exclusive to the case group. Genetic burden risk (GBR) analysis revealed a significantly higher median number of common variants in the case group compared to controls (p = 0.035). Genetic analysis identified variants in genes involved in contractile cardiac and cytoskeletal proteins (MYH3, ACTC1), extracellular matrix proteins (FBN1, FREM1, HSPG2), ciliary proteins (EVC2, PKD1L1), enzymes (POLG, DNASE1L3), cell-signaling proteins (TGFB2, CCDC22) and transcription factors (NKX2-5, NONO). This study highlights the significant role of genetic burden and gene variants associated with congenital mitral and tricuspid valve anomalies. Our findings reinforce the strong genetic predisposition underlying these malformations, as evidenced by the increased genetic burden in affected individuals compared to controls without CHD.