Down syndrome congenital heart disease: A narrowed region and a candidate gene

Abstract

Purpose: Down syndrome (DS) is a major cause of congenital heart disease (CHD) and the most frequent known cause of atrioventricular septal defects (AVSDs). Molecular studies of rare individuals with CHD and partial duplications of chromosome 21 established a candidate region that included D21S55 through the telomere. We now report human molecular and cardiac data that narrow the DS-CHD region, excluding two candidate regions, and propose DSCAM (Down syndrome cell adhesion molecule) as a candidate gene. Methods: A panel of 19 individuals with partial trisomy 21 was evaluated using quantitative Southern blot dosage analysis and fluorescence in situ hybridization (FISH) with subsets of 32 BACs spanning the region defined by D21S16 (21q11.2) through the telomere. These BACs span the molecular markers D21S55, ERG, ETS2, MX1/2, collagen XVIII and collagen VI A1/A2. Fourteen individuals are duplicated for the candidate region, of whom eight (57%) have the characteristic spectrum of DS-CHD. Results: Combining the results from these eight individuals suggests the candidate region for DS-CHD is demarcated by D21S3 (defined by ventricular septal defect), through PFKL (defined by tetralogy of Fallot). Conclusions: These data suggest that the presence of three copies of gene(s) from the region is sufficient for the production of subsets of DS-CHD. This region does not include genes located near D21S55, previously proposed as a "DS critical region," or the genes encoding collagens VI and XVIII. Of the potential gene candidates in the narrowed DS-CHD region, DSCAM is notable in that it encodes a cell adhesion molecule, spans more than 840 kb of the candidate region, and is expressed in the heart during cardiac development. Given these properties, we propose DSCAM as a candidate for DS-CHD. Genetics in Medicine, 2001:3(2):91-101.

Functional Status of Thyroid Gland in Hospitalized Children With Down’s Syndrome

“…Advanced maternal age is associated with high incidence of Trisomy, it is also reflected in our study. 12 We found no sex difference (Pearson chi-square:0.568 and p-value: 0.451) with regard to the incidence of hypothyroidism, which is consistent with the findings of other studies. 4,13 This is in contrast to previous observations among both children and adults with hypothyroidism, in whom a female preponderance was found.…”

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

“…6 We report the clinical findings of 7/12 cases for partial monosomy 21. All the cases reported (7/7) were described with mental retardation.…”

“…5 For example, it was previously concluded that a DS heart defect critical region maps to an B5.2 Mb region. 6 Although the notion of a DSCR has gained some acceptance in DS research, the data supporting it remain controversial. Further, recent work on a mouse model either trisomic or monosomic for the syntenic DSCR found no evidence that the region was required to produce the characteristic facial phenotype, 11 and that it was necessary, but not sufficient, for the hippocampal phenotype seen in DS.…”

Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies

“…Highly prevalent Down syndrome anomalies include mental retardation, Alzheimer's-like pathologies, craniofacial dysmorphologies, and atrioventricular septal (AV) defects in the heart (Reeves et al, 2001). Genetic mapping studies have defined a minimal region of chromosome 21, termed the Down syndrome critical region, which contains the gene(s) necessary to produce Down syndrome features (McCormick et al, 1989;Korenberg et al, 1990Korenberg et al, , 1994Delabar et al, 1993;Barlow et al, 2001). The complexity and variability of the Down syndrome phenotype suggests that several genes contribute to different aspects of the syndrome.…”