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

Abstract

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-cM 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.

Figure 1

Pedigree of the family; circles represent females, squares males. Unaffected individuals are depicted with empty symbols and deceased individuals are indicated by slashes with age of death in years. Right-sided filled symbols denote individuals with low atrial rhythm, left-sided filled symbols represent those with congenital heart defects or persistent left superior vena cava, right upper quarter filled symbols represent individuals with horizontal P-wave frontal axis and left lower quarter filled symbols indicate those with rhythm/conduction disturbances with normal P-wave frontal axis. Dots denote obligate carriers. The proband is indicated by an arrow. Haplotypes are depicted under each individual, and the disease haplotype is demarcated by the box. For reasons of clarity not all parents are shown, markers according to the Marshfield map.

Figure 2

(a) ECG of patient IV-9 at age 32 years with isolated low atrial rhythm. The P-wave is negative in leads II, III and aVF. (b) Transverse computed tomography image of individual III-3. Persistent left superior vena cava (arrow). AA, ascending aorta; DA, descending aorta.

Figure 3

Graphs of the multipoint parametric (a) and nonparametric, NPL (b) LOD scores of microsatellite markers on chromosome 9 for various analysis scenarios. The area of linkage is enlarged, depicting the position of markers and candidate genes screened by sequencing.