Objective: To explore the TPO, DUOX2 and DUOXA2 genotypes and phenotypes of children with permanent congenital hypothyroidism(PCH) suspected dyshormonogenesis in Guangzhou, identified and treated at Guangzhou Newborn Screening Center. Six of them were born between 2011 and 2012. Method: Retrospectively analyzed the clinical data of 9 children with PCH suspected dyshormonogenesis. Genetic analysis of TPO, DUOX2 and DUOXA2 genes were performed with Sanger sequencing. Result: Of the 9 patients, four were identified variants in TPO gene including three cases with biallelic variants and one case with monoallelic variant. Novel c. 1784G>C( p. R595T) variant in TPO was predicted to be damaging by SIFT and PolyPhen-2. Four patients harbored monoallelic known variants in DUOX2 gene and the other one harbored heterozygous known mutation c. 738C>G(p.Y246X) in DUOXA2 gene.Two adolescent patients with biallelic variants in TPO gene showed classical PCH phenotypes with thyroid goiter or nodules. The six patients with monoallelic variant in TPO, DUOX2 or DUOXA2 presented variable phenotypes. Among the 433 578 newborns in the 2011-2012 cohort, there were 156 cases of CH. Six of these cases were PCH suspected dyshormonogenesis, among which 1 case was confirmed TPO biallelic variants and 5 cases were monoallelic variants of TPO, DUOX2, or DUOXA2 genes. Conclusion: TPO and DUOX2 variants are the common molecular pathogenesis in children with PCH suspected dyshormonogenesis. Monoallelic variants in TPO, DUOX2 or DUOXA2 are associated with PCH and showed wide variability in their phenotypes. The novel variant p. R595T in TPO is probably a pathologic variant. The prevalence of PCH caused by TPO gene defects is rare in Guangzhou.
目的：探讨疑似甲状腺素合成障碍性永久性先天性甲状腺功能减低症(congenital hypothyroidism，CH)患儿TPO、DUOX2及DUOXA2基因突变特点及其与临床表型的关系。 方法：回顾分析广州市新生儿筛查中心诊治随访的9例(含2011—2012年筛查获诊的6例)疑似甲状腺素合成障碍性永久性CH患儿临床资料，采用Sanger测序方法对TPO、DUOX2及DUOXA2基因所有外显子及其相邻内含子进行测序，分析基因型与临床表型的关系。 结果： 9例患儿中，4例检出TPO基因突变(其中3例为双等位基因突变，1例为单等位基因突变)，4例检出DUOX2单等位基因致病性突变，1例为DUOXA2基因已知致病突变c.738C>G(p.Y246X)携带者。TPO基因新突变c.1784G>C(p.R595T)经SIFT及PolyPhen－2软件预测提示致病性可能性大。2例TPO双等位基因突变的青春期患儿呈典型永久性CH表型，伴有甲状腺肿大或结节。6例TPO、DUOX2或DUOXA2单等位基因突变者表现为不同程度的甲状腺功能低下。2011—2012年广州市433 578名新生儿CH筛查确诊156例CH，6例疑似甲状腺素合成障碍性永久性CH，其中1例确诊为TPO双等位基因缺陷，其余均为TPO、DUOX2或DUOXA2突变携带者。 结论： TPO及DUOX2基因突变是广州地区疑似甲状腺素合成障碍性永久性CH患儿较常见的分子发病基础，TPO、DUOX2及DUOXA2单等位基因突变与CH发病有关，其临床表现具有显著异质性。广州地区TPO基因突变所致永久性CH罕见，新突变p.R595T致病性可能性大。.
Keywords: Congenital hypothyroidism; Gene; Mutation.