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

Abstract

Context: Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leadsmost often to definitive infertility with adverse health outcomes. Very recently, genes involvedin deoxyribonucleic acid (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. Chromosomalbreaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC).Setting and patients: The proposita presented intrauterine and postnatal growth retardation,multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growthhormone (GH) from age 14 to 18 years.Results: We identified a novel nonsense variant in exon 9 of the minichromosome maintenancecomplex component 8 gene (MCM8) NM_001281522.1: c0.925C > T/p.R309*yielding either atruncated protein or nonsense-mediated messenger ribonucleic acid decay.The variant was homozygous in the daughter and heterozygous in the mother. MMC inducedDNA breaks and aberrant metaphases in the patient's lymphoblastoid cells. The mother's cellshad intermediate but significantly higher chromosomal breaks compared with a control.Conclusion: We describe a novel phenotype of syndromic POI related to a novel truncatingMCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) areassociated with an MCM8 genetic defect, making the screening of this gene necessarybefore starting GH therapy in patients with POI with short stature, especially in a familial orconsanguineous context. Appropriate familial monitoring in the long term is necessary, andfertility preservation should be considered in heterozygous siblings to avoid rapid follicularatresia.