复发性及孤立性内含子FGFR1变异是先天性低促性腺激素性性腺功能减退症诊断不足的原因

文献信息

中文摘要

背景： 先天性低促性腺激素性性腺功能减退症（CHH）是一种遗传异质性疾病，其特征是由于促性腺激素释放激素缺乏而导致青春期缺失或延迟以及不育。虽然FGFR1的功能丧失变异是CHH最常见的已知遗传原因，但诊断筛查通常集中于编码外显子，可能忽略非编码区的致病变异。
方法： 我们研究了4个无亲缘关系的CHH家系。家系1包括一位母亲和3个女儿，表现出不同的生殖表型和嗅觉缺失的不完全外显；家系3由一名患有CHH和嗅觉缺失的女孩组成；家系2和4由表现为CHH和嗅觉缺失的男性患者组成。遗传学研究使用外显子组或基因组测序进行。利用从外周血单核细胞提取的RNA对已识别的内含子变异进行实验表征。对复发性变异进行了基于外显子组或基因组测序的单倍型分析。
结果： 在家系1至3中，我们鉴定出FGFR1中一个复发性杂合内含子变异：c.92-19G > A。RNA分析证实，该变异产生一个隐蔽剪接受体位点，导致17个内含子核苷酸的包含，从而产生提前终止密码子。单倍型分析显示该变异在每个家系中独立发生。在家系4中，鉴定出FGFR1中一个不同的杂合内含子变异，该变异被证明导致内含子15保留并提前终止。
结论： 我们的发现表明，FGFR1中的内含子变异是CHH的可能原因，并可导致从嗅觉正常的CHH到严重Kallmann综合征的多样临床表型，包括女性患者的显著表现。

英文摘要

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder characterized by absent or delayed puberty and infertility due to gonadotropin-releasing hormone deficiency. While loss-of-function variants in FGFR1 are the most commonly known genetic cause of CHH, diagnostic screening typically focuses on coding exons, potentially overlooking pathogenic variants in noncoding regions.
METHODS: We investigated 4 unrelated families with CHH. Family 1 included a mother and 3 daughters presenting with variable reproductive phenotypes and incomplete penetrance of anosmia; Family 3 consisted of a girl with CHH and anosmia; and Families 2 and 4 consisted of male patients who presented with CHH and anosmia. Genetic investigations were done using either exome or genome sequencing. Experimental characterization of the identified intronic variants was conducted using RNA extracted from peripheral blood mononuclear cells. Exome or genome sequencing-based haplotyping was performed for the recurring variant.
RESULTS: In Families 1 to 3, we identified a recurring heterozygous intronic variant in FGFR1: c.92-19G > A. RNA analysis confirmed that this variant generates a cryptic splice acceptor site, leading to the inclusion of 17 intronic nucleotides, resulting in a premature stop codon. Haplotype analysis revealed the variant occurred independently in each family. In Family 4, a distinct heterozygous intronic variant was identified in FGFR1, which was shown to cause intron 15 retention with premature termination.
CONCLUSION: Our findings demonstrate that intronic variants in FGFR1 are a possible cause of CHH and can lead to diverse clinical phenotypes ranging from normosmic CHH to severe Kallmann syndrome, including significant presentation in female patients.