Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder

Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease‐associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type‐2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom‐designed MLPA‐ and PCR‐based approach was used to identify 23 novel NAHR‐mediated type‐2 NF1 deletions. Breakpoint analysis of these 23 type‐2 deletions, together with 17 NAHR‐mediated type‐2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type‐2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253‐bp) as well as the existence of a novel NAHR hotspot of 1.9‐kb (termed PRS4). This hotspot harbored 20% (8/40) of the type‐2 deletion breakpoints and contains the 253‐bp recurrent breakpoint region BR6 in which four independent type‐2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non‐B DNA‐forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene. Hum Mutat 33:1599–1609, 2012. © 2012 Wiley Periodicals, Inc.