A gene for total anomalous pulmonary venous return (TAPVR-1) maps to the centromere of chromosome 4

Total anomalous pulmonary venous return (TAPVR) is a cyanotic congenital heart defect with an incidence of 1/15,000 live births. It usually occurs without a family history, and has a low recurrrence risk (3-5%). In TAPVR the pulmonary veins fail to enter the left atrium, and instead drain into the right atrium or one of its venous tributaries. Without surgical correction, TAPVR has a high mortality rate in the first year of life. Last year we reported a large Utah-Idaho family in which non-syndromic TAPVR appears to be inherited as an autosomal dominant trait with incomplete penetrance and variable expression. This is the largest reported case of familial TAPVR (14 affected individuals), a fact that allowed us to map a major gene for this low penetrance anomaly. Because the reduced penetrance forced us to classify all unaffected relatives as phenotype {open_quotes}unknown{close_quotes}, the preliminary linkage search included only 34 obligate carriers, affected individuals, and unrelated spouses. Linkage mapping with polymorphic microsatellite markers localizes the TAPVR-1 locus to a 30 cM interval on chromosome 4p13-q11 (max. lod = 6.51 at {theta}=0.0). A vascular endothelial growth factor receptor thought to have a role in vasculogenesis also maps near the centromere and is therefore amore » candidate for the TAPVR-1 gene. The possibility of genetic anticipation in the pedigree prompted a search for expanded trinucleotide repeats using repeat expansion detection (RED). We found no evidence of expanded repeats associated with TAPVR in this family.« less