Abstract：
BACKGROUND: Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro.
OBJECTIVE: The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported.
METHODS: Cross-sectional study.
METHODS: University Research Laboratory.
METHODS: 158 patients with nHH/KS.
METHODS: Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing.
METHODS: P/LP variants in nHH/KS genes.
RESULTS: ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant.
CONCLUSIONS: Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.
OBJECTIVE: The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported.
METHODS: Cross-sectional study.
METHODS: University Research Laboratory.
METHODS: 158 patients with nHH/KS.
METHODS: Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing.
METHODS: P/LP variants in nHH/KS genes.
RESULTS: ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant.
CONCLUSIONS: Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.
摘要：
背景：低促性腺激素性腺功能减退症（HH）是由于促性腺激素释放激素（GnRH）作用受损导致青春期缺失和不孕。在40-50%的nHH/KS中，至少有44个基因被鉴定为具有遗传变异。2-20%的人认为是双基因疾病，但并非所有变体都已在体外表征。
目的：单基因和双基因nHH/KS中致病性（P）/可能致病性（LP）变异的患病率低于报道。
方法：横断面研究。
方法：大学研究实验室。
方法：158例nHH/KS患者。
方法：进行外显子组测序（ES），并使用Varsome过滤44个已知基因的变体，并通过Sanger测序进行确认。
方法：nHH/KS基因中的P/LP变异。
结果：ES产生了>370,000个变体，从其中过滤了44个基因的变体。在10个基因（ANOS1，CHD7，DUSP6，FGFR1，HS6ST1，KISS1，PROKR2，SEMA3A，SEMA3E,TACR3),足以引起疾病，在30/158（19％）患者中发现。只有2/158（1.2％）患者具有双基因变体组合：男性具有半合子ANOS1和杂合TACR3变体，男性具有杂合SEMA3A和SEMA3E变体。两名患者（1.2％）具有复合杂合GNRHR（常染色体隐性遗传）变异-一个P和一个不确定意义的变异（VUS）。5例患者（3.2％）在GNRHR或TACR3（均为常染色体隐性遗传）中具有杂合P/LP变异，但没有第二种变体。
结论：我们在nHH/KS中P/LP变异的患病率为19%，观察到的双源性为1.2%。这些发现比以前报道的要少，并且可能表示更准确的估计，因为不包括VUS。
目的：单基因和双基因nHH/KS中致病性（P）/可能致病性（LP）变异的患病率低于报道。
方法：横断面研究。
方法：大学研究实验室。
方法：158例nHH/KS患者。
方法：进行外显子组测序（ES），并使用Varsome过滤44个已知基因的变体，并通过Sanger测序进行确认。
方法：nHH/KS基因中的P/LP变异。
结果：ES产生了>370,000个变体，从其中过滤了44个基因的变体。在10个基因（ANOS1，CHD7，DUSP6，FGFR1，HS6ST1，KISS1，PROKR2，SEMA3A，SEMA3E,TACR3),足以引起疾病，在30/158（19％）患者中发现。只有2/158（1.2％）患者具有双基因变体组合：男性具有半合子ANOS1和杂合TACR3变体，男性具有杂合SEMA3A和SEMA3E变体。两名患者（1.2％）具有复合杂合GNRHR（常染色体隐性遗传）变异-一个P和一个不确定意义的变异（VUS）。5例患者（3.2％）在GNRHR或TACR3（均为常染色体隐性遗传）中具有杂合P/LP变异，但没有第二种变体。
结论：我们在nHH/KS中P/LP变异的患病率为19%，观察到的双源性为1.2%。这些发现比以前报道的要少，并且可能表示更准确的估计，因为不包括VUS。
