Chromosome Breakage in the Prader-Willi and Angelman Syndromes Involves Recombination between Large, Transcribed Repeats at Proximal and Distal Breakpoints

Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately.67-1/10,000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.

Phenotypic manifestations of copy number variation in chromosome 16p13.11

“…As there was clustering of breakpoints in the regions of LCRs, it is likely that they were mediated by non-allelic homologous recombination (NAHR). Many genomic disorders mediated by NAHR such as Prader Willi 28 and Smith-Magenis syndrome, 29 have variable sizes of deletions because of recombination between alternate LCRs.…”

Prader-Willi syndrome

“…90,91 Genes in the 15q11.2-q13 region. The 15q11.2-q13 region can be roughly divided into four distinct regions that are delineated by three common deletion breakpoints, 92 which lie within segmental duplications 93 (Figure 3): (1) a proximal nonimprinted region between the two common proximal breakpoints (BP1 and BP2) containing four biparentally expressed genes, NIPA1, NIPA2, CYF1P1, and GCP5. 94 (2) The "PWS paternal-only expressed region" containing five polypeptide coding genes (MKRN3, MAGEL2, NECDIN, and the bicistronic SNURF-SNRPN); C15orf2 (an intronless gene that is biallelically expressed in testis but only expressed from the paternal allele in brain); a cluster of C/D box small nucleolar RNA genes (snoRNAs); and several antisense transcripts (including the The following additional descriptions pertain to the diagnostic criteria.…”

“…The majority of individuals with deletions have one of two common proximal breakpoints (BP1 or BP2) and a common distal breakpoint (BP3). 92,93 These recurrent common interstitial deletions measure approximately 5-6 Mb in size and are due to the presence of multiple copies of tandemly repeated sequences at the common breakpoints (BP1, BP2, and BP3) flanking the deleted region. These low copy repeat sequences stretch for approximately 250-400 kb and can cause nonhomologous pairing and aberrant recombination of the 15q11.2-q13 region during meiosis, leading to deletions (causing PWS or AS depending on parental origin), duplications (both maternal and paternal), triplications, and inverted dup (15 can also determine the parental origin in this region and is discussed further below.…”

Clinical and genetic aspects of Angelman syndrome

“…Three chromosomal break points (proximal BP1, BP2, and a distal BP3) are involved in most AS-causing deletion events involving 15q11.1-q13, and these deletions span approximately 5-7 Mb [97][98][99] (Fig. 2).…”