Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.
Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.
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用原位腺体甲状腺功能减退症中八个已知的病因基因的全面筛查。
DOI：
10.1210/jc.2016-1879
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Schoenmakers N
中科院分区：
文献类型：
--
作者：
Nicholas AK;Serra EG;Cangul H;Alyaarubi S;Ullah I;Schoenmakers E;Deeb A;Habeb AM;Almaghamsi M;Peters C;Nathwani N;Aycan Z;Saglam H;Bober E;Dattani M;Shenoy S;Murray PG;Babiker A;Willemsen R;Thankamony A;Lyons G;Irwin R;Padidela R;Tharian K;Davies JH;Puthi V;Park SM;Massoud AF;Gregory JW;Albanese A;Pease-Gevers E;Martin H;Brugger K;Maher ER;Chatterjee VK;Anderson CA;Schoenmakers N
较低的TSH筛查临界值使先天性甲状腺功能减退症（CH）的确诊率增加了一倍，特别是原位腺体（GIS）的病例。虽然在已知的激素生成障碍基因或TSHR突变的基础上的CH与GIS的一些情况下，这八个基因的系统筛选以前没有进行。我们的目的是评估8个已知致病基因（TG、TPO、DUOX 2、DUOXA 2、SLC 5A 5、SLC 26 A4、IYD和TSHR）突变在CH伴GIS病例中的贡献和分子谱。我们筛选了49例CH与GIS从34个种族不同的家庭，使用下一代测序。通过计算机模拟评估新突变的致病性。29例病例可能存在致病突变。单基因缺陷（19例）最常见的涉及TG（12例）、TPO（4例）、DUOX 2（2例）和TSHR（1例）。10例病例携带三等位基因（双基因）突变：TG和TPO（1例）; SLC 26 A4和TPO（3例），DUOX 2和TG（6例）。新的变异总体上包括15个TG、6个TPO和3个DUOX 2突变。20例未明确遗传基础，其中14例有家族史。CH伴GIS的病因仍然难以捉摸，在一个家族性病例富集的队列中，只有59%可归因于TSHR或已知的激素生成障碍相关基因的突变。双等位基因TG或TPO突变最常见的严重CH的基础。三等位基因缺陷是常见的，未来的分离研究，在较大的激酶，以评估其对可变表型的贡献。高比例（约41%）的未解决或模棱两可的情况下，提出新的遗传病因，仍有待阐明。对49例先天性甲状腺功能减退症患者进行TG、TPO、DUOX 2、DUOXA 2、SLC 5A 5、SLC 26 A4、IYD和TSHR基因筛查。59%得到解决，包括三等位基因突变病例。
Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated. TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD and TSHR genes were screened in 49 cases of congenital hypothyroidism with eutopic gland-in-situ. 59% were solved including cases with triallelic mutations.
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影响因子：
3.2
作者：
Corbetta, Carlo;Weber, Giovanna;Persani, Luca
通讯作者：
Persani, Luca
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
1.4
作者：
Satoh, Mari;Aso, Keiko;Saji, Tsutomu
通讯作者：
Saji, Tsutomu
影响因子：
5.8
作者：
Hulur, Imge;Hermanns, Pia;Grasberger, Helmut
通讯作者：
Grasberger, Helmut
DOI：
10.1111/j.1432-1033.1996.0125h.x
发表时间：
1996-08-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Molina, F;Bouanani, M;Granier, C
通讯作者：
Granier, C