Institute of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
Hum Genet. 2021 Dec;140(12):1635-1649. doi: 10.1007/s00439-021-02363-3. Epub 2021 Sep 18.
An estimated 5-11% of patients with neurofibromatosis type-1 (NF1) harbour large deletions encompassing the NF1 gene and flanking regions. These NF1 microdeletions are subclassified into type 1, 2, 3 and atypical deletions which are distinguishable from each other by their extent and by the number of genes included within the deletion regions as well as the frequency of mosaicism with normal cells. Most common are type-1 NF1 deletions which encompass 1.4-Mb and 14 protein-coding genes. Type-1 deletions are frequently associated with overgrowth, global developmental delay, cognitive disability and dysmorphic facial features which are uncommon in patients with intragenic pathogenic NF1 gene variants. Further, patients with type-1 NF1 deletions frequently exhibit high numbers of neurofibromas and have an increased risk of malignant peripheral nerve sheath tumours. Genes located within the type-1 NF1 microdeletion interval and co-deleted with NF1 are likely to act as modifiers responsible for the severe disease phenotype in patients with NF1 microdeletions, thereby causing the NF1 microdeletion syndrome. Genotype/phenotype correlations in patients with NF1 microdeletions of different lengths are important to identify such modifier genes. However, these correlations are critically dependent upon the accurate characterization of the deletions in terms of their extent. In this review, we outline the utility as well as the shortcomings of multiplex ligation-dependent probe amplification (MLPA) to classify the different types of NF1 microdeletion and indicate the importance of high-resolution microarray analysis for correct classification, a necessary precondition to identify those genes responsible for the NF1 microdeletion syndrome.
据估计，5-11%的神经纤维瘤病 1 型（NF1）患者携带包含 NF1 基因和侧翼区域的大片段缺失。这些 NF1 微缺失分为 1 型、2 型、3 型和非典型缺失，它们通过缺失区域的大小、缺失区域内包含的基因数量以及正常细胞镶嵌的频率来区分。最常见的是 1 型 NF1 缺失，其包含 1.4-Mb 和 14 个编码蛋白的基因。1 型缺失常与过度生长、全面发育迟缓、认知障碍和非典型面部特征相关，这些特征在 NF1 基因内致病性变异患者中不常见。此外，1 型 NF1 缺失患者常表现出大量神经纤维瘤，并增加了发生恶性外周神经鞘瘤的风险。位于 1 型 NF1 微缺失区间内并与 NF1 共缺失的基因可能作为修饰基因，负责 NF1 微缺失患者的严重疾病表型，从而导致 NF1 微缺失综合征。不同长度 NF1 微缺失患者的基因型/表型相关性对于鉴定这些修饰基因非常重要。然而，这些相关性严重依赖于对缺失区域大小的准确描述。在这篇综述中，我们概述了多重连接依赖性探针扩增（MLPA）在分类不同类型 NF1 微缺失中的应用及其局限性，并指出了高分辨率微阵列分析对于正确分类的重要性，这是鉴定导致 NF1 微缺失综合征的基因的必要前提。
