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.

Supplemental materials for associated paper.