前激动素受体2罕见序列变异引起的先天性性腺功能减退症：单中心队列的分子遗传学、临床表型和治疗结果

摘要(中文译文)

关于携带前动力蛋白受体2罕见序列变异的先天性低促性腺激素性性腺功能减退症患者，其促生育治疗结局及精子生成持续时间的数据有限。我们旨在描绘一个大型中国先天性低促性腺激素性性腺功能减退症队列中PROKR2的罕见序列变异谱，并描述相关的临床表型和治疗结局。此外，我们还比较了携带PROKR2罕见序列变异的先天性低促性腺激素性性腺功能减退症患者与在已知先天性低促性腺激素性性腺功能减退症相关基因中未发现罕见序列变异的患者之间的生殖表型和治疗结局。研究纳入了7例携带PROKR2罕见序列变异的无亲缘关系先天性低促性腺激素性性腺功能减退症先证者（4例为Kallmann综合征，3例为嗅觉正常的先天性低促性腺激素性性腺功能减退症）。采用靶向下一代测序鉴定这些患者的PROKR2变异，并通过Sanger测序进行验证。根据美国医学遗传学与基因组学学会指南评估所发现的PROKR2罕见序列变异的致病性。回顾性评估并比较携带PROKR2罕见序列变异患者与在已确定的先天性低促性腺激素性性腺功能减退症相关基因中未发现罕见序列变异患者的基线临床特征和治疗结局。我们发现了一个新的PROKR2罕见序列变异（p.Y154*，无义突变）。根据美国医学遗传学与基因组学学会指南，4个罕见序列变异被归类为可能致病性。6例携带PROKR2罕见序列变异并接受促性腺激素治疗的男性患者均在平均1.28年后实现了精子生成。携带PROKR2罕见序列变异患者与在已知先天性低促性腺激素性性腺功能减退症相关基因中未发现罕见序列变异的患者之间，基线临床特征和精子生成结局均未观察到统计学显著差异。我们观察到，携带PROKR2罕见序列变异的男性先天性低促性腺激素性性腺功能减退症患者与在先天性低促性腺激素性性腺功能减退症相关基因中未发现罕见序列变异的患者之间，生殖表型或精子生成结局缺乏显著差异的证据，但这一发现受到我们治疗队列中PROKR2罕见序列变异携带者数量较少的严重限制。一个新PROKR2罕见序列变异的发现扩展了先天性低促性腺激素性性腺功能减退症患者中PROKR2的变异谱。

Abstract

Limited data are available regarding the fertility-inducing treatment outcomes and spermatogenic duration in congenital hypogonadotropic hypogonadism patients carrying prokineticin receptor 2 rare sequence variants. We aimed to delineate the rare sequence variant profiles of PROKR2 in a large Chinese cohort with congenital hypogonadotropic hypogonadism, and to characterize the associated clinical phenotypes and therapeutic outcomes. In addition, the reproductive phenotypes and therapeutic outcomes were compared between patients with congenital hypogonadotropic hypogonadism who harbored PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. Seven unrelated congenital hypogonadotropic hypogonadism probands carrying PROKR2 rare sequence variants (four with Kallmann syndrome and three with normosmic congenital hypogonadotropic hypogonadism) were included. PROKR2 variants in these patients were identified using targeted next-generation sequencing and verified using Sanger sequencing. The pathogenicity of the identified PROKR2 rare sequence variants was assessed according to the American College of Medical Genetics and Genomics guidelines. Baseline clinical characteristics and therapeutic outcomes were retrospectively evaluated and compared between patients with PROKR2 rare sequence variants and those lacking the identified rare sequence variants in established congenital hypogonadotropic hypogonadism-associated genes. We identified a novel PROKR2 rare sequence variant (p.Y154*, a nonsense mutation). Four rare sequence variants were classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. Spermatogenesis was achieved in all six male patients with PROKR2 rare sequence variants who received gonadotropin therapy following an average of 1.28 years. No statistically significant differences were observed in the baseline clinical characteristics and spermatogenic outcomes between patients with PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. We observed a lack of evidence for a significant difference in reproductive phenotype or spermatogenic outcomes between male patients with congenital hypogonadotropic hypogonadism and PROKR2 rare sequence variants and those without identified rare sequence variants in congenital hypogonadotropic hypogonadism-associated genes, but this finding is critically limited by the small number of PROKR2 rare sequence variant carriers in our treatment cohort. The identification of a novel PROKR2 rare sequence variant expands the PROKR2 variant spectrum in patients with congenital hypogonadotropic hypogonadism.

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