Meta-analysis Reveals Transcription Factors and DNA Binding Domain Variants Associated with Congenital Heart Defect and Orofacial Cleft

Overview

Journal medRxiv

Date 2025 Feb 20

PMID 39974057

Authors

Raehoon Jeong

Martha L Bulyk

Affiliations

Soon will be listed here.

Abstract

Many structural birth defect patients lack genetic diagnoses because there are many disease genes as yet to be discovered. We applied a gene burden test incorporating 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 (OC) parent-offspring trio cohorts (n = 3,835 and 1,844, respectively). We identified 17 novel candidate CHD genes and 10 novel candidate OC genes, of which many were known developmental disorder genes. Shorter genes were more powered in a " only" analysis as compared to analysis including inherited pLoF variants. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OC, respectively. In total, 30 affected children had a missense variant in a DNA binding domain of a known CHD, OC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OC and their potentially pleiotropic effects in other developmental disorders.

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