Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic.
Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic.
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DOI：
10.3389/fgene.2021.697549
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发表时间：
2021
影响因子：
3.7
通讯作者：
Radovick S
中科院分区：
文献类型：
--
作者：
Jee YH;Gangat M;Yeliosof O;Temnycky AG;Vanapruks S;Whalen P;Gourgari E;Bleach C;Yu CH;Marshall I;Yanovski JA;Link K;Ten S;Baron J;Radovick S
先天性垂体功能减退症通常是偶发性的。在大多数患者中，病因仍然未知。我们研究了13名儿童散发性先天性垂体功能减退症。非内分泌性、非家族性特发性身材矮小（NFSS）儿童（n = 19）作为对照组。在先证者和未受影响的父母中进行外显子组测序。使用负荷检验方法比较两组中候选变体的数量。首先，我们评估了以前报道的与垂体发育相关的42个基因中罕见的预测致病性变异的频率。先天性垂体功能减退症先证者个体变异的平均数高于NFSS先证者（1.1 vs. 0.21，平均变异/先证者，P = 0.03）。在先天性垂体功能减退症中，垂体相关基因中至少有1个变异的先证者数量高于NFSS（62% vs. 21%，P = 0.03）。其次，我们评估了外显子组中罕见的预测致病性变异的频率（以捕获未发现的原因），这些变异以一种可以解释先证者的单基因病因（从头突变，常染色体隐性遗传或X连锁隐性遗传）的偶发性发生的方式遗传。先天性垂体功能减退症先证者的单基因候选者比NFSS先证者少（1.3 vs. 2.5候选变异/先证者，P = 0.024）。与NFSS（19名先证者中的8名，P = 0.01）不同，我们在之前报道的解释先天性垂体功能减退症表型的基因中没有发现任何候选变体（13名先证者中的0名）。我们的研究结果提供的证据表明，散发性先天性垂体功能减退症的病因学有一个主要的遗传成分，但可能很少是单基因与完全遗传，这表明一个更复杂的病因。
Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband’s condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.
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影响因子：
2.6
作者：
Jean, D;Bernier, G;Gruss, P
通讯作者：
Gruss, P
影响因子：
4.5
作者：
Hughes J;Piltz S;Rogers N;McAninch D;Rowley L;Thomas P
通讯作者：
Thomas P
影响因子：
4.8
作者：
Fatehchand, Kavin;Ren, Li;Butchar, Jonathan P.
通讯作者：
Butchar, Jonathan P.
DOI：
10.20945/2359-3997000000139
发表时间：
2019-04-01
期刊：
Archives of Endocrinology and Metabolism
影响因子：
--
作者：
Correa, Fernanda A.;Nakaguma, Marilena;Mendonça, Berenice B.
通讯作者：
Mendonça, Berenice B.
影响因子：
7.7
作者：
Celen, Cemre;Chuang, Jen-Chieh;Zhu, Hao
通讯作者：
Zhu, Hao