Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.
Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.
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DOI：
10.1530/eje-17-0568
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发表时间：
2018-04
影响因子：
5.8
通讯作者：
Pitteloud N
中科院分区：
文献类型：
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作者：
Cassatella D;Howard SR;Acierno JS;Xu C;Papadakis GE;Santoni FA;Dwyer AA;Santini S;Sykiotis GP;Chambion C;Meylan J;Marino L;Favre L;Li J;Liu X;Zhang J;Bouloux PM;Geyter C;Paepe A;Dhillo WS;Ferrara JM;Hauschild M;Lang-Muritano M;Lemke JR;Flück C;Nemeth A;Phan-Hug F;Pignatelli D;Popovic V;Pekic S;Quinton R;Szinnai G;l'Allemand D;Konrad D;Sharif S;Iyidir ÖT;Stevenson BJ;Yang H;Dunkel L;Pitteloud N
先天性促性腺功能减退症（CHH）和体质性生长和青春期延迟症（CDGP）分别是GnRH缺乏的罕见和常见形式。CDGP和CHH都表现为青春期延迟，在青春期早期区分这两种疾病是有挑战性的。超过30个基因与CHH有关，而CDGP的遗传基础尚不清楚。我们对CHH和CDGP的遗传结构进行了表征和比较，以检验这些疾病之间共享遗传基础的假设。外显子组测序数据用于鉴定CHH （n = 116）、CDGP （n = 72）和对照队列（n = 36 874 ExAC和n = 405 CoLaus）中已知基因的罕见变异。在51%的CHH先证中发现至少一个CHH基因突变，显著高于CDGP （7%, P = 7.6 × 10−11）或对照组（18%,P = 5.5 × 10−12）。同样，相对于CDGP （1.4%, P = 0.002）和对照组（2%,P = 6.4 × 10−7），CHH患者（15%）的少原性（定义为多个基因突变）也很常见。我们的数据表明CDGP和CHH具有不同的遗传谱，这一发现可能有助于在出现青春期延迟的患者中进行鉴别诊断。
Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7). Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.