Copy number variations in the NF1 gene region are infrequent and do not predispose to recurrent type-1 deletions

Abstract

Gross deletions of the NF1 gene at 17q11.2 belong to the group of 'genomic disorders' characterized by local sequence architecture that predisposes to genomic rearrangements. Segmental duplications within regions associated with genomic disorders are prone to non-allelic homologous recombination (NAHR), which mediates gross rearrangements. Copy number variants (CNVs) without obvious phenotypic consequences also occur frequently in regions of genomic disorders. In the NF1 gene region, putative CNVs have been reportedly detected by array comparative genomic hybridization (array CGH). These variants include duplications and deletions within the NF1 gene itself (CNV1) and a duplication that encompasses the SUZ12 gene, the distal NF1-REPc repeat and the RHOT1 gene (CNV2). To explore the possibility that these CNVs could have played a role in promoting deletion mutagenesis in type-1 deletions (the most common type of gross NF1 deletion), non-affected transmitting parents of patients with type-1 NF1 deletions were investigated by multiplex ligation-dependent probe amplification (MLPA). However, neither CNV1 nor CNV2 were detected. This would appear to exclude these variants as frequent mediators of NAHR giving rise to type-1 deletions. Using MLPA, we were also unable to confirm CNV1 in healthy controls as previously reported. We conclude that locus-specific techniques should be used to independently confirm putative CNVs, originally detected by array CGH, to avoid false-positive results. In one patient with an atypical deletion, a duplication in the region of CNV2 was noted. This duplication could have occurred concomitantly with the deletion as part of a complex rearrangement or may alternatively have preceded the deletion.

Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions

“…Whereas most type-2 NF1 deletions are of postzygotic origin, the vast majority of type-1 NF1 deletions with breakpoints located within the NF1-REPs A and C are mediated by interchromosomal NAHR during maternal meiosis [Ló pez-Correa et al, 2000; Steinmann et al, 2008]. This mirrors the origin of the germline microdeletions underlying Williams-Beuren syndrome, DiGeorge syndrome, and Angelman syndrome, which are also predominantly generated by interchromosomal NAHR during either maternal or paternal meiosis [Thomas et al, 2006, and references therein].…”

“…Two common types of recurrent NF1 deletion have been identified that differ in terms of their size and breakpoint location: type-1 NF1 deletions span 1.4-Mb and are mediated by NAHR between LCRs termed NF1-REP A and NF1-REP C [Dorschner et al, 2000;Jenne et al, 2001;Ló pez-Correa et al, 2001]. The majority of type-1 NF1 deletions are maternally inherited germ-line deletions [Ló pezCorrea et al, 2000;Steinmann et al, 2008;Upadhyaya et al, 1998] whose breakpoints are located within two hotspot regions of meiotic recombination termed PRS1 and PRS2 [Forbes et al, 2004;Ló pez-Correa et al, 2001]. By contrast, type-2 NF1 deletions encompass only 1.2-Mb and their breakpoints are located within the SUZ12 gene (MIM] 606245) and its pseudogene SUZ12P, which immediately flank the NF1-REPs (Fig.…”

Tissue-specific differences in the proportion of mosaic large NF1 deletions are suggestive of a selective growth advantage of hematopoietic del(+/−) stem cells

“…Mosaicism was also investigated in patients 3304 and 1860-M with NF1 deletions other than type-2. The breakpoints of the atypical deletion in patient 1860-M were previously identified [Steinmann et al, 2008] whereas the extent of the atypical or type-1 NF1 deletion of patient 3304 has been characterized in this study using FISH (Supp. Fig.…”

“…Two of these six patients had an inherited atypical deletion (patients 1860 and 1860-1) whereas four patients had sporadic NF1 deletions. The deletion in patient 1860 spans 1.3 Mb and is atypical [Steinmann et al, 2008;Supp. Fig.…”

Extended runs of homozygosity at 17q11.2: an association with type-2NF1deletions?

“…Whereas the vast majority of type-1 deletions occur during maternal meiosis and therefore manifest as constitutional deletions in the offspring [Ló pez-Correa et al, 2000;Steinmann et al, 2008;Upadhyaya et al, 1998], type-2 NF1 deletions occur preferentially during early fetal mitotic cell divisions giving rise to somatic mosaicism Steinmann et al, 2007]. These somatic type-2 NF1 deletions therefore provide an ideal model system in which to study the genomic features that could serve to promote mitotic NAHR.…”