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Molecular Genetics and Complex Inheritance of Congenital Heart Disease

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy acc...

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Autores principales: Diab, Nicholas S., Barish, Syndi, Dong, Weilai, Zhao, Shujuan, Allington, Garrett, Yu, Xiaobing, Kahle, Kristopher T., Brueckner, Martina, Jin, Sheng Chih
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307500/
https://www.ncbi.nlm.nih.gov/pubmed/34209044
http://dx.doi.org/10.3390/genes12071020
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author Diab, Nicholas S.
Barish, Syndi
Dong, Weilai
Zhao, Shujuan
Allington, Garrett
Yu, Xiaobing
Kahle, Kristopher T.
Brueckner, Martina
Jin, Sheng Chih
author_facet Diab, Nicholas S.
Barish, Syndi
Dong, Weilai
Zhao, Shujuan
Allington, Garrett
Yu, Xiaobing
Kahle, Kristopher T.
Brueckner, Martina
Jin, Sheng Chih
author_sort Diab, Nicholas S.
collection PubMed
description Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.
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spelling pubmed-83075002021-07-25 Molecular Genetics and Complex Inheritance of Congenital Heart Disease Diab, Nicholas S. Barish, Syndi Dong, Weilai Zhao, Shujuan Allington, Garrett Yu, Xiaobing Kahle, Kristopher T. Brueckner, Martina Jin, Sheng Chih Genes (Basel) Review Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis. MDPI 2021-06-30 /pmc/articles/PMC8307500/ /pubmed/34209044 http://dx.doi.org/10.3390/genes12071020 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Diab, Nicholas S.
Barish, Syndi
Dong, Weilai
Zhao, Shujuan
Allington, Garrett
Yu, Xiaobing
Kahle, Kristopher T.
Brueckner, Martina
Jin, Sheng Chih
Molecular Genetics and Complex Inheritance of Congenital Heart Disease
title Molecular Genetics and Complex Inheritance of Congenital Heart Disease
title_full Molecular Genetics and Complex Inheritance of Congenital Heart Disease
title_fullStr Molecular Genetics and Complex Inheritance of Congenital Heart Disease
title_full_unstemmed Molecular Genetics and Complex Inheritance of Congenital Heart Disease
title_short Molecular Genetics and Complex Inheritance of Congenital Heart Disease
title_sort molecular genetics and complex inheritance of congenital heart disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307500/
https://www.ncbi.nlm.nih.gov/pubmed/34209044
http://dx.doi.org/10.3390/genes12071020
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