Abstract：
BACKGROUND: Primary ovarian insufficiency (POI) affects around 2-4% of women before the age of 40. Genetic factors play an important role in POI. The GDF9 gene has been identified as a significant genetic contributor of POI. However, the pathogenicity and penetrance of GDF9 variants remain uncertain.
METHODS: A next-generation sequencing approach was employed to investigate the entire coding region of the GDF9 gene in a cohort of 1281 patients with POI or diminished ovarian reserve (DOR). The frequency of each identified GDF9 variant was then compared with that of the general population, taking into account the ethnicity of each individual.
RESULTS: By screening the entire coding region of the GDF9 gene, we identified 19 different variants, including 1 pathogenic frameshift variant. In total, 36 patients with POI/DOR (2.8%) carried at least one GDF9 variant. With regard to missense variants, no significant overrepresentation of the most common variants was observed in our POI/DOR cohort in comparison to the general or specific ethnic subgroups. Only one homozygous subject had a frameshift loss of function variant.
CONCLUSIONS: This epidemiological study suggests that the vast majority of heterozygous missense variants could be considered as variants of uncertain significance and the homozygous loss-of-function variant could be considered as a pathogenic variant. The identification of a novel case of a homozygous POI patient with a heterozygous mother carrying the same variant with normal ovarian function strongly suggests that GDF9 syndrome is an autosomal recessive disorder.
METHODS: A next-generation sequencing approach was employed to investigate the entire coding region of the GDF9 gene in a cohort of 1281 patients with POI or diminished ovarian reserve (DOR). The frequency of each identified GDF9 variant was then compared with that of the general population, taking into account the ethnicity of each individual.
RESULTS: By screening the entire coding region of the GDF9 gene, we identified 19 different variants, including 1 pathogenic frameshift variant. In total, 36 patients with POI/DOR (2.8%) carried at least one GDF9 variant. With regard to missense variants, no significant overrepresentation of the most common variants was observed in our POI/DOR cohort in comparison to the general or specific ethnic subgroups. Only one homozygous subject had a frameshift loss of function variant.
CONCLUSIONS: This epidemiological study suggests that the vast majority of heterozygous missense variants could be considered as variants of uncertain significance and the homozygous loss-of-function variant could be considered as a pathogenic variant. The identification of a novel case of a homozygous POI patient with a heterozygous mother carrying the same variant with normal ovarian function strongly suggests that GDF9 syndrome is an autosomal recessive disorder.
摘要：
背景：原发性卵巢功能不全（POI）影响40岁之前约2-4％的女性。遗传因素在POI中起重要作用。GDF9基因已被鉴定为POI的重要遗传贡献者。然而,GDF9变异体的致病性和外显率仍不确定.
方法：采用下一代测序方法研究了1281例POI或卵巢储备功能降低(DOR)患者的GDF9基因的整个编码区。然后将每个鉴定的GDF9变异的频率与普通人群的频率进行比较，考虑到每个人的种族。
结果：通过筛选GDF9基因的整个编码区，我们确定了19种不同的变体，包括1个致病性移码变体。总的来说,36例POI/DOR患者（2.8%）携带至少一种GDF9变异。关于错觉变体，与一般或特定种族亚组相比,在我们的POI/DOR队列中未观察到最常见变异体的显著过度表达.只有一名纯合受试者具有功能变体的移码损失。
结论：这项流行病学研究表明，绝大多数杂合错义变异可被认为是意义不确定的变异，而纯合功能缺失变异可被认为是致病变异。鉴定出一个纯合POI患者的新病例，该患者的杂合母亲携带具有正常卵巢功能的相同变体，这强烈表明GDF9综合征是一种常染色体隐性遗传疾病。
方法：采用下一代测序方法研究了1281例POI或卵巢储备功能降低(DOR)患者的GDF9基因的整个编码区。然后将每个鉴定的GDF9变异的频率与普通人群的频率进行比较，考虑到每个人的种族。
结果：通过筛选GDF9基因的整个编码区，我们确定了19种不同的变体，包括1个致病性移码变体。总的来说,36例POI/DOR患者（2.8%）携带至少一种GDF9变异。关于错觉变体，与一般或特定种族亚组相比,在我们的POI/DOR队列中未观察到最常见变异体的显著过度表达.只有一名纯合受试者具有功能变体的移码损失。
结论：这项流行病学研究表明，绝大多数杂合错义变异可被认为是意义不确定的变异，而纯合功能缺失变异可被认为是致病变异。鉴定出一个纯合POI患者的新病例，该患者的杂合母亲携带具有正常卵巢功能的相同变体，这强烈表明GDF9综合征是一种常染色体隐性遗传疾病。
