CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506, Covilhã, Portugal.
Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Santa Maria, 1649-035, Lisboa, Portugal.
Sci Rep. 2019 Feb 7;9(1):1597. doi: 10.1038/s41598-018-38178-y.
Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of normal pubertal development due to deficient gonadotropin-releasing hormone (GnRH) secretion or action, and is caused by genetic defects in several genes. Mutations in the CHD7 gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH. The aim of this study was to identify CHD7 mutations in patients with CHH. Fifty Portuguese patients with CHH were screened for mutations in the CHD7 gene by DNA sequencing. Eight (16%) patients had CHD7 rare sequence variants that consisted of six missense (p.Gly388Glu, p.His903Pro, p.Thr1082Ile, p.Val1452Leu, p.Asp1854Gly, and p.Arg2065His) and two synonymous (p.Ser559Ser, and p.Ala2785Ala) mutations. Five of these mutations have never been reported before. Three CHD7 mutations occurred in patients that had mutations in additional CHH-genes. This study uncovered novel genetic variants that expand the known spectrum of mutations associated with CHH. The frequency of CHD7 mutations in this cohort was higher than that of other major CHH-genes and confirms the importance of including CHD7 in the genetic testing of CHH, even in the absence of additional CHARGE features.
先天性低促性腺激素性性腺功能减退症（CHH）的特征是由于促性腺激素释放激素（GnRH）分泌或作用不足导致正常青春期发育缺失，是由几个基因的遗传缺陷引起的。CHD7 基因突变会导致 CHARGE 综合征（眼裂、心脏缺陷、后鼻孔闭锁、生长发育迟缓、生殖器发育不全和耳部异常），但也存在于孤立性 CHH 患者中。本研究旨在鉴定 CHH 患者的 CHD7 基因突变。通过 DNA 测序对 50 名葡萄牙 CHH 患者进行 CHD7 基因突变筛查。8 名（16%）患者存在 CHD7 罕见序列变异，包括 6 个错义突变（p.Gly388Glu、p.His903Pro、p.Thr1082Ile、p.Val1452Leu、p.Asp1854Gly 和 p.Arg2065His）和 2 个同义突变（p.Ser559Ser 和 p.Ala2785Ala）。其中 5 种突变以前从未报道过。3 种 CHD7 突变发生在存在其他 CHH 基因突变的患者中。本研究揭示了新的遗传变异，扩大了与 CHH 相关的已知突变谱。该队列中 CHD7 突变的频率高于其他主要 CHH 基因，证实了即使没有额外的 CHARGE 特征，在 CHH 的基因检测中也应包括 CHD7。
