Reproductive Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
Hum Mutat. 2019 Jul;40(7):886-892. doi: 10.1002/humu.23744. Epub 2019 Mar 29.
Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63-related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI.
卵巢早衰是指 40 岁以前出现闭经和促卵泡激素升高，其遗传基础知之甚少。在这里，我们通过全外显子组测序研究了 13 名卵巢早衰（POI）患者。我们鉴定了 PREPL 和 TP63 的致病变异，以及其他潜在的新的 POI 基因的变异。PREPL 缺陷是一种已知的综合征性 POI 的原因，与患者的表型相匹配。TP63 在卵巢生物学中的作用以前已经被提出，但在多器官综合征中已经描述了变体，而不是孤立的 POI。一名孤立性 POI 患者携带无义 TP63 变异体，位于末端外显子，另一名无关患者在同一外显子中携带另一种无义变异体。这些变异体干扰抑制结构域，同时保持激活结构域完整。我们扩展了 TP63 相关疾病的表型谱，为 TP63 提供了新的基因型-表型相关性，并确定了孤立性 POI 的新的遗传原因。
