Centro de Investigación Genética y Genómica. Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Mariscal Sucre Avenue, 170129, Quito, Ecuador.
Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain.
BMC Med Genomics. 2020 Aug 17;13(1):113. doi: 10.1186/s12920-020-00764-3.
Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF).
Here, we present clinical and molecular findings in a 9-year-old girl with CIPA. The high-altitude indigenous Ecuadorian patient presented several health problems such as anhidrosis, bone fractures, self-mutilation, osteochondroma, intellectual disability and Riga-Fede disease. After the mutational analysis of NTRK1, the patient showed a clearly autosomal recessive inheritance pattern with the pathogenic mutation rs763758904 (Arg602*) and the second missense mutation rs80356677 (Asp674Tyr). Additionally, the genomic analysis showed 69 pathogenic and/or likely pathogenic variants in 46 genes possibly related to phenotypic heterogeneity, including the rs324420 variant in the FAAH gene. The gene ontology enrichment analysis showed 28 mutated genes involved in several biological processes. As a novel contribution, the protein-protein interaction network analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix involved in the response to stimulus and nervous system development.
This is the first study that associates clinical, genomics and networking analyses in a Native American patient with consanguinity background in order to better understand CIPA pathogenesis.
先天性无痛无汗症（CIPA）是一种极其罕见的常染色体隐性遗传病，其特征为对疼痛不敏感、无法出汗和智力障碍。CIPA 是由神经营养酪氨酸激酶受体 1 型基因（NTRK1）突变引起的，该基因编码神经生长因子（NGF）的高亲和力受体。
在这里，我们介绍了一名 9 岁 CIPA 女孩的临床和分子发现。这位来自厄瓜多尔高地的土著患者出现了多种健康问题，如无汗症、骨折、自残、骨软骨瘤、智力障碍和 Riga-Fede 病。在对 NTRK1 进行突变分析后，患者表现出明显的常染色体隐性遗传模式，携带致病性突变 rs763758904（Arg602*）和第二个错义突变 rs80356677（Asp674Tyr）。此外，基因组分析显示在 46 个可能与表型异质性相关的基因中存在 69 个致病性和/或可能致病性变异，包括 FAAH 基因中的 rs324420 变异。基因本体富集分析显示 28 个突变基因参与了几个生物学过程。作为一项新的贡献，蛋白质-蛋白质相互作用网络分析表明，NTRK1、SPTBN2 和 GRM6 与疼痛矩阵中的几个涉及对刺激和神经系统发育反应的蛋白质相互作用。
这是第一项在有亲缘关系的美洲原住民患者中进行临床、基因组学和网络分析以更好地了解 CIPA 发病机制的研究。
