Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome.
Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans. It occurs with an estimated frequency of 1 in 4, 000 live births. Most cases occur sporadically, indicating that the deletion is recurrent in the population. More than 90% of patients with VCFS and a 22q11 deletion have a similar 3-Mb hemizygous deletion, suggesting that sequences at the breakpoints confer susceptibility to rearrangements. To define the region containing the chromosome breakpoints, we constructed an 8-kb-resolution physical map. We identified a low-copy repeat in the vicinity of both breakpoints. A set of genetic markers were integrated into the physical map to determine whether the deletions occur within the repeat. Haplotype analysis with genetic markers that flank the repeats showed that most patients with VCFS had deletion breakpoints in the repeat. Within the repeat is a 200-kb duplication of sequences, including a tandem repeat of genes/pseudogenes, surrounding the breakpoints. The genes in the repeat are GGT, BCRL, V7-rel, POM121-like, and GGT-rel. Physical mapping and genomic fingerprint analysis showed that the repeats are virtually identical in the 200-kb region, suggesting that the deletion is mediated by homologous recombination. Examination of two three-generation families showed that meiotic intrachromosomal recombination mediated the deletion.
Edelmann
L
L
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Pandita
R K
RK
Morrow
B E
BE
D000015:Abnormalities, Multiple / Q000235:genetics*; D001483:Base Sequence; D019457:Chromosome Breakage / Q000235:genetics*; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D016172:DNA Fingerprinting; D004062:DiGeorge Syndrome / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D005810:Multigene Family / Q000235:genetics; D010375:Pedigree; D020161:Physical Chromosome Mapping; D011544:Pseudogenes / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome
D005819:Genetic Markers