Castro Sebastián, Brunello Franco G, Sansó Gabriela, Izquierdo Agustín, Zaiat Jonathan, Urrutia Mariela, Martí Marcelo, Rey Rodolfo A, Tellechea Mariana L, Grinspon Romina P
Centro de Investigaciones Endocrinológicas "Dr César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA) e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Buenos Aires, Argentina.
Hum Reprod. 2025 May 1;40(5):904-918. doi: 10.1093/humrep/deaf041.
Which phenotypes can be confidently linked to a genetic etiology in males with congenital hypogonadotropic hypogonadism (CHH) resulting in absent or arrested puberty?
In this systematic review and reclassification of the disease-causing potential of gene variants using the recommendations of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), we found that absent or arrested puberty in males with CHH was linked to 93 genes, of which 29 were unequivocally disease-causing.
The number of genes and phenotype characterizations associated with CHH in males has rapidly increased since the advent of next-generation sequencing technologies; however, the quality of the evidence for the interpretation of the causal relationship of gene variants is limited due to the lack of systematic criteria applied to the assessment of the pathogenic potential of the variants.
STUDY DESIGN, SIZE, DURATION: We performed a systematic review of original articles indexed in PubMed until 5 October 2022 and using the search terms '(('hypogonadotropic hypogonadism' OR Kallmann) AND (sequencing OR mutation OR variant))' limited to 'Humans' and 'English'.
PARTICIPANTS/MATERIALS, SETTING, METHODS: After two investigators undertook the literature search independently, titles and abstracts of all records were reviewed by four of the authors to identify those articles to be included in the full-text review. Clinical data and the association with gene variants were extracted from males with delayed or arrested puberty due to CHH according to the article authors' criteria. Raw sequence variant information was used to reevaluate their pathogenic potential applying the ACMG/AMP guidelines for variant classification with InterVar. Subsequently, we considered the phenotype specificity criteria for sequence variant pathogenicity classification, based on curated genes associated with CHH, and classified patients into three categories: with monogenic disease-causing variants in genes associated with CHH, with variants in genes whose causality is unclear, and with variants that are not disease-causing.
From a total of 1083 records, we included 245 publications with 775 male patients with CHH resulting in absent or arrested puberty, carrying 1001 variants in 93 genes. Gene variants were detected by Sanger sequencing in 61.8% of the cases and by next-generation sequencing (NGS) technologies in the rest. After variant reclassification of causality, 278 individuals were not considered to have a bona fide disease-causing gene variant, and 497 patients were reclassified as carrying at least one disease-causing variant associated with CHH. They carried 503 different disease-causing variants in 29 genes. Spontaneous puberty was absent in 85.5% and arrested in 14.5% of the 497 individuals with CHH carrying bona fide disease-causing variants. In males with absent puberty (complete hypogonadotrophic hypogonadism), FGFR1 and ANOS1 were the most frequently affected genes, accounting for 53.5% of the disease-causing variants. In males with incomplete spontaneous puberty (partial hypogonadotrophic hypogonadism), variants in FGFR1, NR0B1, and GNRHR were found in 70.3% of the cases. Micropenis, cryptorchidism and/or low testicular volume, considered 'red flags' for the diagnosis of CHH, were found in less than 30% of males, with cryptorchidism being more frequently observed in association with variants in FGFR1, ANOS1, KISS1R, SOX10, and GNRH1, and micropenis being more prevalent in patients with variants in TACR3, KISS1R, or GNRH1. Clinical manifestations in non-reproductive organs were found in 39.8% of the patients with bona fide disease-causing variants.
LIMITATIONS, REASONS FOR CAUTION: Because we included studies going back to the initial genetic reports of patients with CHH, results obtained by Sanger sequencing represent a significant proportion of the whole sample, which may be biased by the use of a candidate gene strategy. A subanalysis of cases studied by NGS modified the results only slightly.
This comprehensive synthesis will help clinicians in the guidance of reverse phenotyping once the precise genetic diagnosis is established, and researchers in the design of functional studies to clarify the role of specific sequence variants in the etiology of male CHH. A genetic etiology of CHH in males with absent or arrested puberty should be considered even in the absence of micropenis, cryptorchidism, and/or low testicular volume.
STUDY FUNDING/COMPETING INTEREST(S): This work was partially funded by grants PICT I-A-2018-02972 of Fondo de Promoción Científica y Técnica (FONCYT), PICT A-CAT III2021-73 of Fondo Argentino Sectorial (FONARSEC) and Proyectos de Redes Federales de Alto Impacto 2023 #3 of Ministerio de Ciencia, Tecnología e Innovación, Argentina. Competing interests: None declared.
None declared.
在导致青春期缺失或停滞的先天性低促性腺激素性性腺功能减退（CHH）男性患者中，哪些表型可以明确与遗传病因相关联？
在这项使用美国医学遗传学与基因组学学会（ACMG）和分子病理学协会（AMP）的建议对基因变异的致病潜力进行的系统综述和重新分类中，我们发现CHH男性患者的青春期缺失或停滞与93个基因相关，其中29个基因明确具有致病作用。
自下一代测序技术出现以来，与男性CHH相关的基因数量和表型特征迅速增加；然而，由于缺乏用于评估变异体致病潜力的系统标准，解释基因变异因果关系的证据质量有限。
研究设计、规模、持续时间：我们对截至2022年10月5日在PubMed上索引的原始文章进行了系统综述，使用的搜索词为“(('低促性腺激素性性腺功能减退'或卡尔曼综合征) AND (测序或突变或变异体))”，仅限于“人类”和“英语”。
参与者/材料、设置、方法：两名研究人员独立进行文献检索后，四位作者对所有记录的标题和摘要进行了审查，以确定纳入全文综述的文章。根据文章作者的标准，从因CHH导致青春期延迟或停滞的男性患者中提取临床数据以及与基因变异的关联。使用原始序列变异信息，应用ACMG/AMP变异分类指南和InterVar重新评估其致病潜力。随后，我们基于与CHH相关的经过整理的基因，考虑序列变异致病性分类的表型特异性标准，并将患者分为三类：携带与CHH相关基因的单基因致病变异体、携带因果关系不明确基因变异体、携带非致病变异体。
在总共1083条记录中，我们纳入了245篇出版物，涉及775例因CHH导致青春期缺失或停滞的男性患者，这些患者携带93个基因中的1001个变异体。61.8%的病例通过桑格测序检测到基因变异体，其余病例通过下一代测序（NGS）技术检测到。在对因果关系进行变异重新分类后，278名个体不被认为携带真正的致病基因变异体，497名患者被重新分类为至少携带一个与CHH相关的致病变异体。他们在29个基因中携带503种不同的致病变异体。在497例携带真正致病变异体的CHH个体中，85.5%的个体青春期未出现，14.5%的个体青春期停滞。在青春期缺失（完全性低促性腺激素性性腺功能减退）的男性中，FGFR1和ANOS1是受影响最频繁的基因，占致病变异体的53.5%。在青春期不完全自发出现（部分性低促性腺激素性性腺功能减退）的男性中，70.3%的病例中发现FGFR1、NR0B1和GNRHR基因存在变异。被视为CHH诊断“警示信号”的小阴茎、隐睾症和/或低睾丸体积在不到30%的男性中出现，隐睾症更常与FGFR1、ANOS1、KISS1R、SOX10和GNRH1基因变异相关，小阴茎在TACR3、KISS1R或GNRH1基因变异的患者中更为普遍。在携带真正致病变异体的患者中，39.8%的患者出现非生殖器官的临床表现。
局限性、注意事项：由于我们纳入了可追溯至CHH患者最初遗传报告的研究，通过桑格测序获得的结果在整个样本中占很大比例，这可能因使用候选基因策略而存在偏差。对通过NGS研究的病例进行的亚分析仅对结果产生了轻微影响。
这一全面的综合分析将有助于临床医生在确定精确的基因诊断后进行反向表型分析指导，也有助于研究人员设计功能研究以阐明特定序列变异体在男性CHH病因中的作用。即使没有小阴茎、隐睾症和/或低睾丸体积，也应考虑青春期缺失或停滞的男性CHH的遗传病因。
研究资金/利益冲突：这项工作部分由阿根廷科学技术促进基金（FONCYT）的PICT I - A - 2018 - 02972资助、阿根廷部门基金（FONARSEC）的PICT A - CAT III2021 - 73资助以及阿根廷科学、技术和创新部2023年第3号高影响力联邦网络项目资助。利益冲突：未声明。
未声明。
