Prenatal diagnosis of two fetuses with deletions of 8p23.1, critical region for congenital diaphragmatic hernia and heart defects

Abstract

Microdeletions of 8p23.1 are mediated by low copy repeats and can cause congenital diaphragmatic hernia (CDH) and cardiac defects. Within this region, point mutations of the GATA4 gene have been shown to cause cardiac defects. However, the cause of CDH in these deletions has been difficult to determine due to the paucity of mutations that result in CDH, the lack of smaller deletions to refine the region and the reduced penetrance of CDH in these large deletions. Mice deficient for one copy of the Gata4 gene have been described with CDH and heart defects suggesting mutations in Gata4 can cause the phenotype in mice. We report on the SNP microarray analysis on two fetuses with deletions of 8p23.1. The first had CDH and a ventricular septal defect (VSD) on ultrasonography and a family history of a maternal VSD. Microarray analysis detected a 127-kb deletion which included the GATA4 and NEIL2 genes which was inherited from the mother. The second fetus had an incomplete atrioventricular canal defect on ultrasonography. Microarray analysis showed a 315-kb deletion that included seven genes, GATA4, NEIL2, FDFT1, CTSB, DEFB136, DEFB135, and DEFB134. These results suggest that haploinsufficiency of the two genes in common within 8p23.1; GATA4 and NEIL2 can cause CDH and cardiac defects in humans.

Clinical application of chromosomal microarray analysis for the prenatal diagnosis of chromosomal abnormalities and copy number variations in fetuses with congenital heart disease

“…Emerging evidence has indicated that chromosomal abnormalities and genomic copy number variants (CNVs) are responsible for the pathogenesis of CHD . Numerical chromosomal abnormalities, such as trisomy 21, trisomy 18, and trisomy 13, and also rare causative CNVs at recurrent loci, such as 22q11, 8p23.1, and 1q21.1, have been associated with syndromic CHDs. Moreover, clear Mendelian inheritance for CHDs has been observed in a small proportion of patients with a positive family history for CHDs .…”

Wiskott-Aldrich Syndrome in a Girl Caused by Heterozygous <b><i>WASP</i></b> Mutation and Extremely Skewed X-Chromosome Inactivation: A Novel Association with Maternal Uniparental Isodisomy 6

“…Heterozygous (AB) loci could not be identified. SNP microarray analysis was performed using the Affymetrix Cytoscan HD platform [17] which uses over 743,000 SNP probes and 1,953,000 NPCN probes with a median spacing of 0.88 kb. …”

Prenatal diagnosis of inverted duplication deletion 8p syndrome mimicking trisomy 18

“…Duplications of some part of the olfactory receptor (OR) gene clusters serve as a source for the rearrangements of the short arm of chromosome 8 [Giglio et al, ; Buysse et al, ]. The 8p23.1 region and the GATA4 gene are “hotspots” for fetal heart development, as deletion and duplication of 8p23.1 are associated with heart defects including: atrial and/or ventricular septal defects, double outlet right ventricle, dextrocardia, pulmonary stenosis, and hypoplastic left heart syndrome [Pehlivan et al, ; Keitges et al, ]. Large deletions of 8p23.1 including the GATA4 gene are associated with more severe CHD than heterozygous GATA4 point mutations [Wat et al, ].…”