A novel phenotype combining primary ovarian insufficiency growth retardation and pilomatricomas with MCM8 mutation

Context: Primary Ovarian insufficiency (POI) affects 1% of women under 40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in DNA repair have been shown to cause POI.

Objective: To identify the cause of a familial POI in a consanguineous Turkish family.

Design: Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with Mitomycin (MMC).

Setting and patients: The proposita presented intra-uterine and post-natal growth retardation, multiple pilomatricomas in childhood and primary amenorrhea. She was treated with growth hormone (GH) from 14 to 18 years.

Results: We identified a novel nonsense mutation in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM_001281522.1: c.925C>T/p.R309* yielding a truncated protein devoid of the 531 C-terminal residues.

The mutation was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient’s lymphoblastoid cells. The mother’s cells had intermediate but significantly higher chromosomal breaks compared to a control.

Conclusion: We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 mutation. We show for the first time that spontaneous tumors (pilomatricomas) are associated with MCM8 genetic defect making the screening of this gene necessary before starting GH therapy in POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia.

研究背景：原发性卵巢功能不全（Primary Ovarian Insufficiency, POI）在40岁以下女性中的发病率为1%，常导致永久性不孕及不良健康结局。近期研究表明，参与DNA修复的基因可引发POI。

研究目的：明确一个近亲婚配土耳其家族中家族性POI的致病原因。

研究设计：对先证者及其母亲进行外显子组测序。对经丝裂霉素（MMC）处理的淋巴母细胞系进行染色体断裂分析。

研究对象与场景：先证者存在宫内及产后生长迟缓、儿童期多发毛母质瘤及原发性闭经，14至18岁期间接受生长激素（GH）治疗。

研究结果：我们在微小染色体维持复合物组件8基因（MCM8）NM_001281522.1的第9外显子中发现了一种新型无义突变：c.925C>T/p.R309*，该突变可产生缺失531个C端残基的截短蛋白。
该突变在先证者体内为纯合型，在其母亲体内为杂合型。经MMC处理后，患者的淋巴母细胞系出现DNA断裂及异常分裂中期相。与对照组相比，母亲的细胞系染色体断裂程度处于中间水平但显著升高。

研究结论：我们报道了一种与新型截短型MCM8突变相关的综合征性POI新表型。我们首次证实自发性肿瘤（毛母质瘤）与MCM8基因缺陷相关，这提示对于伴身材矮小的POI患者，尤其是存在家族性或近亲婚配背景的患者，在启动GH治疗前需对该基因进行筛查。长期的家族监测必不可少，同时应考虑对杂合子兄弟姐妹进行生育力保存，以避免快速卵泡闭锁。