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Hypoplastic left heart is a severe human congenital heart defect characterized by left ventricular hypoplasiawith aortic and mitral valve atresia. A genetic etiology is indicated by an association of the hypoplastic left heart phenotype with terminal 11q deletions that span approximately 20 Mb (distal to FRA11B in 11q23). Here we define the breakpoints in four patients with heart defects in association with distal 11q monosomy and refine the critical region to an approximately 9-Mb region distal to D11S1351. Within this critical region we have identified JAM3, a member of the junction adhesion molecule family, as a strong candidate gene for the cardiac phenotype on the basis that it is expressed during human cardiogenesis in the structures principally affected in hypoplastic left heart.

We present a yeast artificial chromosome (YAC) and pulsed-field gel electrophoresis (PFGE) map across the centromere of human chromosome 10 that links expressed sequences in 10p11 to expressed sequences in 10q11.2. This map is the first of its kind to link genes across a human centromere. It consists of a 2.5-Mb YAC contig extending from 10p11 to our previously published 5.35-Mb PFGE map of the centromeric satellite arrays, and a 2.65-Mb YAC contig extending from these satellite arrays to 10q11.2. This map covers approximately 6.5-7% of the total DNA of chromosome 10. Two Généthon genetic markers, D10S578 and D10S604, are included. These markers are only 1 cM apart but are separated by a physical distance of more than 9.2 Mb, including the centromere. This gives a ratio of genetic to physical distance of 0.11 cM/Mb, 9-11 times lower than average estimates for the human genome and chromosome 10. Markers linked to the centromere include the duplicated zinc finger genes ZNF11A, ZNF33A, and ZNF37A (which map to 10p11) and ZNF11B, ZNF33B, and ZNF37B (which map to 10q11.2). Restriction mapping confirms that the genes on each arm lie in opposite orientation with respect to the centromere, consistent with the hypothesis that a pericentric inversion has occurred in this region during primate evolution.

The gene implicated in the development of multiple endocrine neoplasia type 2A, and inherited cancer syndrome transmitted as an autosomal dominant trait, has been mapped by genetic linkage to the pericentromeric region of chromosome 10. To isolate new markers for this region, we constructed cosmid libraries from two radiation hybrids, R104-2D2 and R244-3A1, derived from the hybrid cell line 762-8A, which contains only human chromosomes 10 and Y in a hamster background. 15 refs., 1 tab.