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Identification of Large NF1 Duplications Reciprocal to NAHR ‐Mediated Type‐1 NF1 Deletions
Author(s) -
KehrerSawatzki Hildegard,
Bengesser Kathrin,
Callens Tom,
Mikhail Fady,
Fu Chuanhua,
Hillmer Morten,
Walker Martha E.,
Saal Howard M.,
Lacassie Yves,
Cooper David N.,
Messiaen Ludwine
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22692
Subject(s) - non allelic homologous recombination , breakpoint , gene duplication , biology , segmental duplication , genetics , neurofibromatosis , recombination , gene , genetic recombination , genome , chromosomal translocation , gene family
Approximately 5% of all patients with neurofibromatosis type‐1 ( NF 1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots ( CALS ), L isch nodules, freckling, or neurofibromas, the hallmark signs of NF 1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS . Additionally, patient R 609021 had L isch nodules, whereas patient R 653070 exhibited two inguinal freckles. The mother and sister of patient R 609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS . The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high‐resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination ( NAHR ) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type‐1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type‐1 NF1 deletions and originate from the same NAHR events.