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

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 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

A new syndrome with noncompaction cardiomyopathy, bradycardia, pulmonary stenosis, atrial septal defect and heterotaxy with suggestive linkage to chromosome 6p.

Contains fulltext : 69194.pdf (publisher's version ) (Closed access)We report a three-generation family with nine patients affected by a combination of cardiac abnormalities and left isomerism which, to our knowledge, has not been described before. The cardiac anomalies include non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. The laterality sequence anomalies include left bronchial isomerism, azygous continuation of the inferior vena cava, polysplenia and intestinal malrotation, all compatible with left isomerism. This new syndrome is inherited in an autosomal dominant pattern. A genome-wide linkage analysis suggested linkage to chromosome 6p24.3-21.2 with a maximum LOD score of 2.7 at marker D6S276. The linkage interval is located between markers D6S470 (telomeric side) and D6S1610 (centromeric side), and overlaps with the linkage interval in another family with heterotaxy reported previously. Taken together, the genomic region could be reduced to 9.4 cM (12 Mb) containing several functional candidate genes for this complex heterotaxy phenotype