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<p>Many congenital anomaly patients lack genetic diagnoses because there are many disease genes as yet to be discovered. We applied a gene burden test incorporating de novo predicted-loss-of-function (pLoF) and likely damaging missense variants together with inherited pLoF variants to a collection of congenital heart defect (CHD) and orofacial cleft (OFC) parent-offspring trio cohorts (<i>n</i> = 3835 and 1844, respectively). We identified 17 novel candidate CHD genes and 8 novel candidate OFC genes, of which many were known developmental disorder genes. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OFC, respectively. In total, 30 affected children had a de novo missense variant in a DNA binding domain of a known CHD, OFC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OFC and their potentially pleiotropic effects in other developmental disorders.</p>

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Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft

  • 期刊论文

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  • 发表日期：

    2025年9月29日

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  • Raehoon Jeong,
  • Martha L. Bulyk

摘要

Many congenital anomaly patients lack genetic diagnoses because there are many disease genes as yet to be discovered. We applied a gene burden test incorporating de novo predicted-loss-of-function (pLoF) and likely damaging missense variants together with inherited pLoF variants to a collection of congenital heart defect (CHD) and orofacial cleft (OFC) parent-offspring trio cohorts (n = 3835 and 1844, respectively). We identified 17 novel candidate CHD genes and 8 novel candidate OFC genes, of which many were known developmental disorder genes. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OFC, respectively. In total, 30 affected children had a de novo missense variant in a DNA binding domain of a known CHD, OFC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OFC and their potentially pleiotropic effects in other developmental disorders.