EDA, EDAR, EDARADD and WNT10A allelic variants in patients with ectodermal derivative impairment in the Spanish population
EDA, EDAR, EDARADD and WNT10A allelic variants in patients with ectodermal derivative impairment in the Spanish population
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DOI：
10.1186/s13023-019-1251-x
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发表时间：
2019-12-03
影响因子：
3.7
通讯作者：
Jose Trujillo-Tiebas, Ma
中科院分区：
文献类型：
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作者：
Carmen Martinez-Romero, Maria;Juliana Ballesta-Martinez, Maria;Jose Trujillo-Tiebas, Ma
背景：外胚层发育不良是一组影响两个或两个以上外胚层衍生物发育和/或动态平衡的遗传性疾病。当患者只受到一个外胚层结构受损的影响时，例如在非综合征性牙齿发育不全(NSTA)疾病中，减弱的表型被认为是非综合征性特征。少汗性外胚层发育不良(HED)是最具代表性的ED。X-连锁少汗性外胚叶发育不良(XLHED)是最常见的外胚叶发育不良亚型，发病率为1/50,000-100,000，与EDA基因(Xq12-q13.1)有关，显性和隐性亚型分别涉及EDAR(2q13)和EDARADD(1q42.3)基因。WNT10A基因(2q35)与NSTA相关的频率更高。我们的目标是确定72名西班牙患者的突变谱，这些患者受到一种或多种外胚层衍生性损害的影响，称为HED(63/72)或NSTA(9/72)，以确定四种最常见相关基因的等位基因变异的流行率。对EDA、EDAR、EDARADD和WNT10A基因进行Sanger测序和多重连接依赖探针扩增(MLPA)。结果：共纳入61例儿童和11例成人，其中男性50例，女性22例。儿童和成人的平均年龄分别为5.4岁和40.2岁。在51/72例患者中发现了分子基础，其中47/63例HED患者中EDA是最常见的受累基因，4/9例NSTA患者中大多数有WNT10A的变异。其中EDA变异37/51，WNT10A变异8/51，EDAR变异4/51，EDARADD变异5/51。其中42/51例为X连锁遗传(27/42)，其余为常染色体显性遗传(10/42)或常染色体隐性遗传(5/42)。在NSTA患者中，3/9携带WNT10A致病变异，1/9携带EDA变异。在51名患者中共检测到60个变异，其中46个不同，在这46个变异中，12个是新的。结论：这是迄今为止在西班牙人中进行的唯一一项受ED影响的分子研究。EDA、EDAR、EDARADD和WNT10A基因在70.8%的患者中构成分子基础，在HED和NSTA中的得率分别为74.6%和44.4%。共鉴定出12个新的变异体。WNT10A基因已被确认为第二个候选分子，占非EDA患者的一半和NSTA患者的三分之一。使用下一代测序(NGS)的进一步研究将有助于在剩余的未表现出特征性的西班牙患者中识别其他促成基因。
Background: Ectodermal dysplasias (ED) are a group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives. An attenuated phenotype is considered a non-syndromic trait when the patient is affected by only one impaired ectodermal structure, such as in non-syndromic tooth agenesis (NSTA) disorder. Hypohidrotic ectodermal dysplasia (HED) is the most highly represented ED. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common subtype, with an incidence of 1/50,000-100,000 males, and is associated with the EDA gene (Xq12-q13.1); the dominant and recessive subtypes involve the EDAR (2q13) and EDARADD (1q42.3) genes, respectively. The WNT10A gene (2q35) is associated more frequently with NSTA.Our goal was to determine the mutational spectrum in a cohort of 72 Spanish patients affected by one or more ectodermal derivative impairments referred to as HED (63/72) or NSTA (9/72) to establish the prevalence of the allelic variants of the four most frequently associated genes. Sanger sequencing of the EDA, EDAR, EDARADD and WNT10A genes and multiplex ligation-dependent probe amplification (MLPA) were performed.Results: A total of 61 children and 11 adults, comprising 50 males and 22 females, were included. The average ages were 5.4 and 40.2 years for children and adults, respectively. A molecular basis was identified in 51/72 patients, including 47/63 HED patients, for whom EDA was the most frequently involved gene, and 4/9 NSTA patients, most of whom had variants of WNT10A. Among all the patients, 37/51 had variants of EDA, 8/51 had variants of the WNT10A gene, 4/51 had variants of EDAR and 5/51 had variants of EDARADD. In 42/51 of cases, the variants were inherited according to an X-linked pattern (27/42), with the remaining showing an autosomal dominant (10/42) or autosomal recessive (5/42) pattern. Among the NSTA patients, 3/9 carried pathogenic variants of WNT10A and 1/9 carried EDA variants. A total of 60 variants were detected in 51 patients, 46 of which were different, and out of these 46 variants, 12 were novel.Conclusions: This is the only molecular study conducted to date in the Spanish population affected by ED. The EDA, EDAR, EDARADD and WNT10A genes constitute the molecular basis in 70.8% of patients with a 74.6% yield in HED and 44.4% in NSTA. Twelve novel variants were identified. The WNT10A gene has been confirmed as the second molecular candidate that has been identified and accounts for one-half of non-EDA patients and one-third of NSTA patients. Further studies using next generation sequencing (NGS) will help to identify other contributory genes in the remaining uncharacterized Spanish patients.