Data from: 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.