title: Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease.
abstract: Congenital heart disease (CHD), comprising structural or functional abnormalities present at birth, is the most common birth defect in humans. Reduced expression of connexin40 (Cx40) has been found in association with atrial fibrillation, and deletion of Cx40 in a mouse model causes various structural heart abnormalities in 18% of heterozygotes. We screened 505 unrelated CHD cases for deletions or duplications of the Cx40 gene (GJA5) by real-time quantitative PCR, in order to determine whether altered copy number of this gene may be associated with a cardiac phenotype in humans. Dosage of Cx40 flanking genes (ACPL1 and Cx50 gene, GJA8) was determined by real-time PCR for all apparent positive cases. In total, 3 cases were found to carry deletions on chromosome 1q21.1 spanning ACPL1, Cx40, and Cx50 genes. Absence of heterozygosity was observed in all 3 index cases over a 1.5- to 3-Mb region. Samples from the parents of two cases were obtained, and microsatellites across 1q21.1 were genotyped. One of the apparently unaffected parents was found to carry this deletion. All 3 index cases presented with obstruction of the aortic arch as the common structural cardiac malformation, and had no consistent dysmorphic features. Genotyping of 520 unrelated normal controls for this deletion was negative. We hypothesize that this 1q21.1 multigene deletion is associated with a range of cardiac defects, with anomalies of the aortic arch being a particular feature.
authors.affiliation: Department of Medical Genetics, University of Alberta Edmonton, Alberta, Canada.
authors.forename: Jesse
authors.initials: J
authors.lastname: Christiansen
authors.forename: John D
authors.initials: JD
authors.lastname: Dyck
authors.forename: Basil G
authors.initials: BG
authors.lastname: Elyas
authors.forename: Margaret
authors.initials: M
authors.lastname: Lilley
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Bamforth
authors.forename: Mark
authors.initials: M
authors.lastname: Hicks
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sprysak
authors.forename: Robert
authors.initials: R
authors.lastname: Tomaszewski
authors.forename: Shelagh M
authors.initials: SM
authors.lastname: Haase
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Vicen-Wyhony
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Somerville
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities* / Q000196:embryology; D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics* / Q000648:ultrastructure; D003199:Computer Systems; D017630:Connexins / Q000172:deficiency / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats; D023421:Models, Animal; D019683:Penetrance; D016133:Polymerase Chain Reaction; D000097003:Gap Junction alpha-5 Protein; D000099264:Connexin 50
chemical_list: D000135:Acid Phosphatase; D017630:Connexins; D005136:Eye Proteins; D000097003:Gap Junction alpha-5 Protein; D000099264:Connexin 50; C459340:ACP6 protein, human