Journal Article

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q

Wilde, Arthur A M, Mathijssen, Inge B, Baars, Marieke J H, Postma, Alex V, Mulder, Barbara J M, Lekanne dit Deprez, Ronald H, Lam, Jan, van de Meerakker, Judith B A, van Engelen, Klaartje, Mannens, Marcel M A M, Moorman, Antoon F M

2011

Overview

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21–33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-c M critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region ( INVS , TMOD1 , TGFBR1 , KLF4 , IPPK , BARX1 , PTCH1 , MEGF9 and S1PR3 ) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

• Publisher: Springer International Publishing,Nature Publishing Group
• Subject: 631/208/207 / 631/443/592 / 692/699/75/1539 / Adolescent / Adult / Aged / Aged, 80 and over / Automation / Bioinformatics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cardiac arrhythmia / Cardiology / Cardiology. Vascular system / Child / Child, Preschool / Chromosome 9 / Chromosomes / Chromosomes, Human, Pair 9 - genetics / Classical genetics, quantitative genetics, hybrids / Comparative Genomic Hybridization / Congenital heart diseases. Malformations of the aorta, pulmonary vessels and vena cava / Cytogenetics / Defects / Deoxyribonucleic acid / DNA / Echocardiography / EKG / Electrocardiography / Embryology / Female / Fundamental and applied biological sciences. Psychology / Gene Expression / Gene mapping / General aspects. Genetic counseling / Genes / Genes, Dominant - genetics / Genetic Linkage / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Genomics / Genotype & phenotype / Heart / Heart Atria - physiopathology / Heart Defects, Congenital - genetics / Human / Human Genetics / Humans / Infant / Infant, Newborn / KLF4 protein / Linkage analysis / Male / Medical genetics / Medical records / Medical sciences / Middle Aged / Molecular and cellular biology / Morphology / Mutation / Mutation - genetics / Nkx2.5 protein / NMR / Nuclear magnetic resonance / Patients / Pediatrics / Pedigree / Phenotypes / Sinuses / Tetralogy of Fallot / Young Adult