Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Hum Mutat. 2011 Feb;32(2):213-9. doi: 10.1002/humu.21418.
Mosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harboring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisposition syndrome and the frequency of mosaicism. Seven of the 14 mosaic NF1 deletions were type-2, whereas four were putatively type-1, and three were atypical. Two of the four probable type-1 deletions were confirmed as such by breakpoint-spanning PCR or SNP analysis. Both deletions were associated with a generalized manifestation of NF1. Independently, we identified a third patient with a mosaic type-1 NF1 deletion who exhibited segmental NF1. Together, these three cases constitute the first proven mosaic type-1 deletions so far reported. In two of these three mosaic type-1 deletions, the breakpoints were located within PRS1 and PRS2, previously identified as hotspots for nonallelic homologous recombination (NAHR) during meiosis. Hence, NAHR within PRS1 and PRS2 is not confined to meiosis but may also occur during postzygotic mitotic cell cycles.
嵌合体是 1 型神经纤维瘤病（NF1）的一个重要特征，因为它会影响临床表现和遗传风险。我们使用 FISH 和 MLPA 对 3500 名 NF1 患者进行筛查，发现 146 名个体携带 NF1 大片段缺失，其中 14 名（9.6%）存在体细胞嵌合体。NF1 缺失患者嵌合体率高，支持该癌症易感性综合征中新突变率高与嵌合体频率之间存在直接关系的假说。14 例嵌合体 NF1 缺失中有 7 例为 2 型，4 例可能为 1 型，3 例为非典型。4 例可能的 1 型缺失中有 2 例通过断点跨越 PCR 或 SNP 分析得到证实。这两个缺失都与 NF1 的广泛表现相关。此外，我们还独立发现了第三位携带 NF1 嵌合体缺失的患者，表现为 NF1 节段性缺失。这三个病例共同构成了迄今为止报道的首例明确的 NF1 嵌合体 1 型缺失。在这三个 NF1 嵌合体缺失中有两个，断裂点位于 PRS1 和 PRS2 内，这两个区域先前被鉴定为减数分裂中非等位基因同源重组（NAHR）的热点。因此，PRS1 和 PRS2 内的 NAHR 不仅局限于减数分裂，也可能发生在合子后有丝分裂细胞周期中。
