Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Genes (Basel). 2022 Nov 26;13(12):2218. doi: 10.3390/genes13122218.
Neurological phenotypes such as intellectual disability occur in almost half of patients with neurofibromatosis 1 (NF1). Current genotype-phenotype studies have failed to reveal the mechanism underlying this clinical variability. Despite the presence of pathogenic variants of NF1, modifier genes likely determine the occurrence and severity of neurological phenotypes. Exome sequencing data were used to identify genetic variants in 13 NF1 patients and 457 healthy controls, and this information was used to identify candidate modifier genes underlying neurological phenotypes based on an optimal sequence kernel association test. Thirty-six genes were identified as significant modifying factors in patients with neurological phenotypes and all are highly expressed in the nervous system. A review of the literature confirmed that 19 genes including , , and are clearly associated with the alteration of neurological functioning and development. Our study revealed the enrichment of rare variants of 19 genes closely related to neurological development and functioning in NF1 patients with neurological phenotypes, indicating possible modifier genes and variants affecting neurodevelopment. Further studies on rare genetic variants of candidate modifier genes may help explain the clinical heterogeneity of NF1.
神经纤维瘤病 1 型（NF1）患者几乎有一半会出现智力残疾等神经表型。目前的基因型-表型研究未能揭示这种临床变异性的机制。尽管存在 NF1 的致病性变异，但修饰基因可能决定了神经表型的发生和严重程度。使用外显子组测序数据，对 13 名 NF1 患者和 457 名健康对照者的遗传变异进行了鉴定，并基于最佳序列核关联测试，利用这些信息鉴定了神经表型潜在的候选修饰基因。鉴定出 36 个与神经表型相关的基因作为显著的修饰因子，所有这些基因在神经系统中均有高度表达。文献综述证实，包括 、 和 在内的 19 个基因显然与神经功能和发育的改变有关。我们的研究揭示了 NF1 患者神经表型中与神经发育和功能密切相关的 19 个基因的罕见变异富集，表明可能存在影响神经发育的修饰基因和变异。对候选修饰基因罕见遗传变异的进一步研究，可能有助于解释 NF1 的临床异质性。
