Genomic disorders contribute significantly to genetic disease and, as detection methods improve, greater numbers are being defined. Paralogous low copy repeats (LCRs) mediate many of the chromosomal rearrangements that underlie these disorders, predisposing chromosomes to recombination errors. Deletions of proximal 22q11.2 comprise the most frequently occurring microdeletion syndrome, DiGeorge/Velocardiofacial syndrome (DGS/VCFS), in which most breakpoints have been localized to a 3 Mb region containing four large LCRs. Immediately distal to this region, there are another four related but smaller LCRs that have not been characterized extensively. We used paralog-specific primers and long-range PCR to clone, sequence, and examine the distal deletion breakpoints from two patients with de novo deletions mapping to these distal LCRs. Our results present definitive evidence of the direct involvement of LCRs in 22q11 deletions and map both breakpoints to the BCRL module, common to most 22q11 LCRs, suggesting a potential region for LCR-mediated rearrangement both in the distal LCRs and in the DGS interval. These are the first reported cases of distal 22q11 deletions in which breakpoints have been characterized at the nucleotide level within LCRs, confirming that distal 22q11 LCRs can and do mediate rearrangements leading to genomic disorders.[Supplemental material is available online at www.genome.org. The sequence data have been submitted to GenBank under accession nos. EF025176-EF025177.]Chromosome 22q11 shows a high frequency of de novo genomic rearrangement. This instability is attributed to the presence of several large paralogous low copy repeats (LCRs) or segmental duplications (SDs), each containing a complex modular structure and a high degree of sequence identity (>96%) over large stretches of the repeat . The LCRs apparently mediate aberrant interchromosomal exchanges during meiosis (Saitta et al. 2004), and 22q11 deletions, which occur in up to 1:4000 live births (Burn and Goodship 1996), are among the most frequent constitutional rearrangements. Other chromosomes are also known to contain similar "rearrangementpromoting" low copy repeats that are implicated in mediating genomic disorders. Examples of such well-known genetic disorders include Prader-Willi and Angelman syndromes, Williams syndrome, NF1 microdeletions, Sotos syndrome, Smith-Magenis syndrome, and the reciprocal deletions and duplications of Charcot Marie Tooth and HNPP (for reviews, see Emanuel and Shaikh 2001;.There are a total of eight LCRs within 22q11. The four proximal LCRs have been extensively characterized, given their involvement in recurrent rearrangements of 22q11 that lead to DGS/VCFS (Edelmann et al. 1999;Shaikh et al. 2001) and Cat eye syndrome (CES) (McTaggart et al. 1998). We have previously referred to the four proximal LCRs as LCR-A through LCR-D based on their chromosomal order, with LCR-A being closest to the centromere . These proximal LCRs are larger than the distal ones and have a complex modular structure. LCR-A and LCR...

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