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.

Delineation of the 9q31 deletion syndrome: Genomic microarray characterization of two patients with overlapping deletions

“…Several other conditions with features somewhat similar to the ones described in our cases have been mapped to the SRO described here: Congenital heart defects type 3 (OMIM 614954), an autosomal dominant condition (van de Meerakker et al, ), and an autosomal dominant form of hypertensive nephropathy (OMIM 608026), in a 4‐generation African American family (Chung et al, ). Although these genome‐wide linkage studies showed strong evidence of linkage to this region (multipoint maximum LOD scores of 4.1 and 5.4 by van de Meerakker et al and Chung et al, respectively), no causative genes have been identified yet.…”

Exome Sequencing and Genome-Wide Linkage Analysis in 17 Families Illustrate the Complex Contribution of TTN Truncating Variants to Dilated Cardiomyopathy

“…Secondly, our genome-wide linkage approach could also have identified regions containing common susceptibility or modifying variants, again that would not have been detected by our exome analysis approach. We note recent prior evidence of linkage to congenital heart defects and low atrial rhythm to this region, 26 suggesting the possibility of cardiovascular modifying variants located here.…”

A novel conserved enhancer at zebrafish zic3 and zic6 loci drives neural expression

“…24,25 Comparative genomics-based approaches have emerged as reliable tools for predicting noncoding genomic features that harbor transcriptional regulatory elements, even in the absence of knowledge about the detailed characteristics of individual cis-regulatory elements. Among the Zic family, Zic3 plays a key role in development and disease.…”

“…Studies have shown that the loss of Zic3 function leads to congenital developmental defects, including heterotaxy and multiple types of congenital heart defects. 24,25 Comparative genomics-based approaches have emerged as reliable tools for predicting noncoding genomic features that harbor transcriptional regulatory elements, even in the absence of knowledge about the detailed characteristics of individual cis-regulatory elements. 3,4,[26][27][28] Two critical steps have been suggested to be necessary to ascertain a functional CNE: (a) carefully selecting the species that are compared and (b) choosing the appropriate length of genomic intervals.…”