Investigation of a critical chromosome 1q congenital heart disease region

Abstract

Chromosomal rearrangements with in 1q42-44 give rise to similar patterns of developmental abnormalities.  Cardiac defects are a common feature and are the predominant cause of death. Such cases argue for the presence of a crucial cardiac developmental disease gene with in this region;  haploinsufficiency of which causes aberrant cardiac development.  A positional candidate strategy was adopted to identify disease-susceptibility genes.  There is currently little molecular data with in the literature to allow the delineation of a critical CHD region within 1q42-44 for targeting candidate genes.  To address this, molecular analysis as carried out on eleven patients with known 1q deletions.  The results obtained suggested that there may be two CHD critical regions within 1q42-44.  To refine the critical regions, CHD patients with normal karyotypes were investigated for submicroscopic deletions using loss-of-heterozygosity analysis.  None were found.  It became apparent that the introduction of a high-throughput, high-resolution technology would facilitate the identification of submicroscopic deletions with in 1q42-44. The novel technique of microarray-comparative genomic hybridisation was therefore established and validated with a known 1q deletion patient.  Genes mapping to the 1q disease intervals were assessed for CHD candidacy.  The basement membrane protein, nidogen-1, was identified as a strong candidate gene.  Mutation screening of nidogen-1 was undertaken in CHD patients.  Direct sequencing identified 10 nucleotide changes. None of these were thought to be pathogenic.

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