Gomes Maria E S, Kanazawa Thatiane Y, Riba Fernanda R, Pereira Natálya G, Zuma Maria C C, Rabelo Natana C, Sanseverino Maria T, Horovitz Dafne D G, Llerena Juan C, Cavalcanti Denise P, Gonzalez Sayonara
Laboratório de Medicina Genômica, Departamento de Genética Médica.
Departamento de Genética Médica, Grupo de Displasias Esqueléticas, FCM-UNICAMP, São Paulo, Brazil.
Mol Syndromol. 2018 Feb;9(2):92-99. doi: 10.1159/000486697. Epub 2018 Feb 2.
Mutations in the fibroblast growth factor receptor 3 gene () cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TDI/TDII). In this study, we performed a genetic study of 123 Brazilian patients with these phenotypes. Mutation hotspots of the gene were PCR amplified and sequenced. All cases had recurrent mutations related to ACH, HCH, TDI or TDII, except for 2 patients. One of them had a classical TDI phenotype but a typical ACH mutation (c.1138G>A) in combination with a novel c.1130T>C mutation predicted as being pathogenic. The presence of the second c.1130T>C mutation likely explained the more severe phenotype. Another atypical patient presented with a compound phenotype that resulted from a combination of ACH and X-linked spondyloepiphyseal dysplasia tarda (OMIM 313400). Next-generation sequencing of this patient's DNA showed double heterozygosity for a typical de novo ACH c.1138G>A mutation and a maternally inherited c.6del mutation. All mutations were confirmed by Sanger sequencing. A pilot study using high-resolution melting (HRM) technique was also performed to confirm several mutations identified through sequencing. We concluded that for recurrent mutations, HRM can be used as a faster, reliable, and less expensive genotyping test than Sanger sequencing.
成纤维细胞生长因子受体3基因（）突变可导致软骨发育不全（ACH）、软骨发育低下（HCH）以及致死性骨发育不全I型和II型（TDI/TDII）。在本研究中，我们对123例具有这些表型的巴西患者进行了基因研究。对该基因的突变热点进行了PCR扩增和测序。除2例患者外，所有病例均有与ACH、HCH、TDI或TDII相关的复发性突变。其中1例具有典型的TDI表型，但存在典型的ACH突变（c.1138G>A），同时伴有一个预测为致病性的新的c.1130T>C突变。第二个c.1130T>C突变的存在可能解释了更严重的表型。另一名非典型患者表现出一种复合表型，该表型由ACH和X连锁迟发性脊椎骨骺发育不良（OMIM 313400）组合而成。对该患者的DNA进行二代测序显示，其典型的新发ACH c.1138G>A突变和母系遗传的c.6del突变呈双杂合状态。所有突变均通过Sanger测序得到证实。还进行了一项使用高分辨率熔解（HRM）技术的初步研究，以确认通过测序鉴定出的几种突变。我们得出结论，对于复发性突变，与Sanger测序相比，HRM可作为一种更快、更可靠且成本更低的基因分型检测方法。
