What’s new in genetics of congenital heart defects

Review published: 01 December 2016 doi: 10.3389/fped.2016.00120 W Maria Cristina Digilio1* and Bruno Marino2 1 Medical Genetics, Bambino Gesù Pediatric Hospital, Rome, Italy, 2 Pediatric Cardiology, Department of Pediatrics, Sapienza University, Rome, Italy Edited by: Oswin Grollmuss, University of Paris-Sud, France Reviewed by: Giuseppe Limongelli, Second University of Naples, Italy Robert Joseph Dabal, University of Alabama at Birmingham, USA *Correspondence: Maria Cristina Digilio Specialty section: This article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Pediatrics Epidemiological studies, clinical observations, and advances in molecular genetics are contributing to the understanding of the etiology of congenital heart defects (CHDs). Several phenotype–genotype correlation studies have suggested that specific morphogenetic mechanisms put in motion by genes can result in a specific cardiac phenotype. The use of new technologies has increased the possibility of identification of new genes and chromosomal loci in syndromic and non-syndromic CHDs. There are a number of methods available for genetic research studies of CHDs, including cytogenetic analysis, linkage and association studies, copy number variation (CNV) and DNA micro-array analysis, and whole exome sequencing. The altered dosage of contiguous genes included inside CNVs can produce new syndromic CHDs, so that several different new genomic conditions have been identified. These include duplication 22q11.2 syndrome, distal 22q11.2 deletion syndrome, deletion and duplication 1q21.1, and deletion 1p36 syndrome. Molecular techniques such as whole exome sequencing have lead to the identification of new genes for monogenic syndromes with CHD, as for example in Adams–Oliver, Noonan, and Kabuki syndrome. The variable expressivity and reduced penetrance of CHDs in genetic syndromes is likely influenced by genetic factors, and several studies have been performed showing the involvement of modifier genes. It is not easy to define precisely the genetic defects underlying non-syndromic CHDs, due to the genetic and clinical heterogeneity of these malformations. Recent experimental studies have identified multiple CNVs contributing to non-syndromic CHD. The number of identified genes for non-syndromic CHDs is at this time limited, and each of the identified genes has been shown to be implicated only in a small proportion of CHD. The application of new technologies to specific cases of CHD and pedigrees with familial recurrence and filtering genes mapping in CNV regions can probably in the future add knowledge about new genes for non-syndromic CHDs. Keywords: genetics, congenital heart defect, syndrome, chromosome, genetic counseling Received: 18 June 2016 Accepted: 19 October 2016 Published: 01 December 2016 INTRODUCTION Citation: Digilio MC and Marino B (2016) What Is New in Genetics of Congenital Heart Defects? Front. Pediatr. 4:120. doi: 10.3389/fped.2016.00120 Epidemiological studies, clinical observations, and advances in molecular genetics are contributing to the understanding of the etiology of congenital heart defects (CHDs). The majority of CHDs are occurring as isolated malformations, while approximately 25–30% of them are associated with extracardiac anomalies, in the setting of large or submicroscopic chromosomal anomalies, Mendelian disorders, and malformation associations (1–3). Some types of CHD, such as atrioventricular canal Frontiers in Pediatrics | www.frontiersin.org 1 December 2016 | Volume 4 | Article 120 Digilio and Marino Genetics of CHD defect (AVCD) and interrupted aortic arch (IAA), are more frequently found in association with genetic syndromes, whereas other types are prevalently isolated defects (tricuspid atresia, transposition of the great arteries, and pulmonary atresia). Several phenotype–genotype correlation studies have suggested that specific morphogenetic mechanisms put in motion by genes can result in a specific cardiac phenotype (4). Clinical implications are resulting from these studies, since distinct cardiac anatomic subtypes may help in suggesting accurate diagnoses, which can be confirmed by molecular testing. It should be considered that it is not easy to define precisely the genetic defects underlying CHDs, particularly non-syndromic types, due to the genetic and clinical heterogeneity of these malformations. Multiple parallel approaches are needed for the exploration of the potential loci etiologically related to CHDs. Rapid advances in genetic technologies have substantially improved the possibility to detect new genes and chromosomal regions for CHDs. There are a number of methods available for genetic research studies of CHDs, including cytogenetic analysis, linkage and association studies, copy number variation (CNV) and DNA micro-array analysis, and whole exome sequencing. The use of new technologies has increased the possibility of identification of new genes and chromosomal loci in syndromic and non-syndromic CHDs. or from highly homologous genes that misalign during meiosis. CNVs can be identified using arrayCGH or genomic microarrays that assess single-nucleotide polymorphisms (SNPs). The altered dosage of contiguous genes included inside CNVs can produce new syndromic CHDs, so that several different new genomic conditions have been identified. Duplication 22q11.2 Syndrome The duplication 22q11.2 syndrome is the reciprocal product of the 3-Mb chromosomal region deleted in DiGeorge/velocardiofacial syndrome (between LCRA and LCRD) (5, 6). The most frequently reported features are mental retardation, learning difficulties, ADHD, growth retardation, and facial anomalies. CHDs, visual and hearing impairment, seizures, microcephaly, ptosis, and urogenital abnormalities have also been reported. The prevalence of CHD in duplication 22q11.2 is lower in comparison to that of deletion 22q11.2, and the spectrum of CHDs wider, including defects belonging to different pathogenetic pathways (septal defects, conotruncal heart defect, and left-sided obstructive lesions). The molecular basis leading to CHD is to be elucidated, considering the overexpression of the TBX1 gene and the possible interaction with other genes inside and outside the 22q11.2 chromosomal region. Distal 22q11.2 Deletion Syndrome The distal 22q11.2 deletion syndrome is a new genomic disorder mapping at the telomeric end of the common DiGeorge/22q11.2 deleted region (7). Clinical features of the 22q11.2 distal deletion syndrome include developmental delay, facial anomalies, low birth weight, skeletal anomalies, and CHDs. Anatomic types of CHD include ventricular septal defects, truncus arteriosus, double outlet right ventricle, aortic anomalies, and left ventricular noncompaction (8). Particularly, left ventricular non-compaction with aortic valve anomalies has been recently reported as useful diagnostic marker for the syndrome (9). Genes functionally interacti (...truncated)