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NKX2‐6 related congenital heart disease: Biallelic homeodomain‐disrupting variants and truncus arteriosus
Author(s) -
Ritter Alyssa,
Werner Petra,
Latney Brande,
Krock Bryon L.,
Santani Avni,
Bedoukian Emma,
Skraban Cara M.,
Deardorff Matthew A.,
Goldmuntz Elizabeth
Publication year - 2020
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61550
Subject(s) - truncus arteriosus , homeobox , phenocopy , biology , phenotype , genetics , tbx1 , genetic heterogeneity , truncus , great arteries , medicine , homeobox protein nkx 2.5 , cardiology , heart disease , gene , anatomy , promoter , tetralogy of fallot , gene expression
Congenital heart defects (CHD) are the most common birth defect and are both clinically and genetically heterogeneous. Truncus arteriosus (TA), characterized by a single arterial vessel arising from both ventricles giving rise to the coronary, pulmonary and systemic arteries, is rare and only responsible for 1% of all CHD. Two consanguineous families with TA were previously identified to have homozygous nonsense variants within the gene NKX2‐6 . NKX2‐6 is a known downstream target of TBX1 , an important transcriptional regulator implicated in the cardiac phenotype of 22q11.2 microdeletion syndrome. Herein, we report two siblings with TA presumably caused by compound heterozygous NKX2‐6 variants without a history of consanguinity. Two in‐house cohorts with conotruncal defects (CTD) were sequenced for variants in NKX2‐ 6 and no additional cases of biallelic NKX2‐6 variants were identified. The similar phenotype of these cases, and the clustering of variants that likely result in a truncated protein that disrupts the homeobox domain, suggest that biallelic loss of function for NKX2‐6 is a rare genetic etiology for TA in particular, and possibly other types of CHD.