Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report.
Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report.
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由于同一等位基因上 FGFR3 跨膜结构域的两个从头变异导致严重软骨发育不全：病例报告。
DOI：
10.1002/mgg3.1148
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发表时间：
2020
影响因子：
2
通讯作者：
Kitoh H.
中科院分区：
文献类型：
--
作者：
Nagata T;Matsushita M;Mishima K;Kamiya Y;Kato K;Toyama M;Ogi T;Ishiguro N;Kitoh H.
背景软骨发育不全（ACH）是短肢骨骼发育不良的最常见形式，是由成纤维细胞生长因子受体3（FGFR3）基因的功能获得性突变引起的。超过 97% 的患者由 FGFR3 基因的 p.G380R 杂合突变所致。我们在此介绍了一名儿童，其 FGFR3 中的同一等位基因有两种新生变异，一种是常见的 p.G380R 突变，另一种是新型 p.S378N 变异。 方法 一名非近亲健康父母所生的 3 岁日本女孩表现出比典型 ACH 更严重的临床和放射学表型，包括严重的短肢身材矮小，干骺端和骨骺有明显的骨化缺陷、脑积水和由于枕骨大孔狭窄、长期肺发育不全以及粗大运动发育显着延迟而导致颈髓受压。从先证者中提取基因组 DNA，并进行全外显子组测序。随后通过桑格测序证实了这些变异。结果突变分析表明先证者的FGFR3基因中存在p.S378N (c.1133G>A)和p.G380R (c.1138G>A)变异。这两种变异均未在她的父母中检测到，因此被认为是新生变异。开发了等位基因特异性 PCR 以确定这些突变是在相同等位基因（顺式）上还是在不同等位基因（反式）上。用突变型1133A引物生成的PCR产物中发现了c.1138G>A突变，但在野生型1133G的产物中未检测到c.1138G>A突变，证实p.S378N和p.G380R变体位于同一等位基因（顺式）上。结论这是第二例在同一等位基因的跨膜域中存在两个FGFR3变体的病例。 p.S378N 变体可能对具有 p.G380R 突变的激活受体产生附加作用，并改变蛋白质功能，这可能是造成本病例严重表型的原因。
BackgroundAchondroplasia (ACH), the most common form of short‐limbed skeletal dysplasia, is caused by gain‐of‐function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. More than 97% of patients result from a heterozygous p.G380R mutation in theFGFR3gene. We present here a child who had two de novo variants in theFGFR3on the same allele, a common p.G380R mutation and a novel p.S378N variant.MethodsA 3‐year‐old Japanese girl born from non‐consanguineous healthy parents showed more severe clinical and radiological phenotypes than classic ACH, including severe short‐limbed short stature with marked ossification defects in the metaphysis and epiphysis, hydrocephalus and cervicomedullary compression due to foramen magnum stenosis, prolonged pulmonary hypoplasia, and significant delay in the gross motor development. Genomic DNA was extracted from the proband and whole‐exome sequencing was performed. The variants were subsequently confirmed by Sanger sequencing.ResultsMutation analysis demonstrated that the proband had p.S378N (c.1133G>A) and p.G380R (c.1138G>A) variants in theFGFR3gene. Both variants were not detected in her parents and therefore considered de novo. An allele‐specific PCR was developed in order to determine whether these mutations were on the same allele (cis) or on different alleles (trans). The c.1138G>A mutation was found in the PCR product generated with the primer for the mutant 1133A, but it was not detected in the product with the wild‐type 1133G, confirming that p.S378N and p.G380R variants were located on the same allele (cis).ConclusionThis is the second case who had twoFGFR3variants in the transmembrane domain on the same allele. The p.S378N variant may provide an additive effect on the activating receptor with the p.G380R mutation and alter the protein function, which could be responsible for the severe phenotype of the present case.