New Genetic Insights into Congenital Heart Disease

Abstract

There has been remarkable progress in understanding the genetic basis of cardiovascular malformations. Chromosome microarray analysis has provided a new tool to understand the genetic basis of syndromic cardiovascular malformations resulting from microdeletion or microduplication of genetic material, allowing the delineation of new syndromes. Improvements in sequencing technology have led to increasingly comprehensive testing for aortopathy, cardiomyopathy, single gene syndromic disorders, and Mendelian-inherited congenital heart disease. Understanding the genetic etiology for these disorders has improved their clinical recognition and management and led to new guidelines for treatment and family-based diagnosis and surveillance. These new discoveries have also expanded our understanding of the contribution of genetic variation, susceptibility alleles, and epigenetics to isolated congenital heart disease. This review summarizes the current understanding of the genetic basis of syndromic and non-syndromic congenital heart disease and highlights new diagnostic and management recommendations.

Association analysis identifies new risk loci for congenital heart disease in Chinese populations

“…CHD may occur as a part of many recognized chromosomal and Mendelian syndromes 7,8 , however, in 75% of cases it manifests as a non-syndromic condition and may result from a multifactorial inheritance model that involves a multitude of susceptibility genes with low-(common variants) or intermediate-penetrance mutations (rare variants) 9 . To date, several genome-wide association studies (GWASs) have achieved success in deciphering the genetic basis of CHD [10][11][12] .…”

Modifying Mendel

“…In the majority of cases, the variant is inherited from an unaffected parent, but in vitro or in vivo functional testing, when available, demonstrates the deleterious nature of the variant. 3,13 These findings illustrate the need to move beyond an expectation of Mendelian inheritance or complete segregation with disease when identifying alleles contributing to human CVMs.…”

“…These include the group of Noonan, Costello, and Cardiofaciocutaneous syndromes resulting from mutations in genes coding for proteins of the Ras pathway, and Holt-Oram syndrome which is caused by mutations in the gene TBX5. [2][3][4] Article see p 301…”

A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect

“…To date, the amount of genes related to CHD including ASD has been identified (Andersen et al, 2013): (1) transcription factors and co-factors, e.g., GATA4 (OMIM 600576), NKX2-5 (OMIM 600584), TBX5 (OMIM 601620), and TBX20 (OMIM 606061); (2) ligands-receptors, e.g., CRELD1 (OMIM 607170); (3) structure protein of sarcomere, e.g., MYH6 (OMIM 160710), MYH7 (OMIM 160760), and ACTC1 (OMIM 102540) (Posch et al, 2010b;Wessels and Willems, 2010;Ware and Jefferies, 2012;Andersen et al, 2013;Fahed et al, 2013).…”