Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature

BACKGROUND: Minichromosome maintenance complex component 8 (MCM8) is responsible for homologous recombination and DNA double‐strand breaks (DSBs) repair and is the cause of primary ovarian insufficiency (POI), which is seldom diagnosed in adolescents and children. METHODS: Whole‐exome sequencing was performed in a 13‐year‐old girl, and Sanger sequencing was used to identify potentially pathogenic variants in her sister (aged 6 years and 7 months) and parents. To identify potential pathogenic mutations, DSBs were induced by mitomycin C (MMC), and the DNA repair capacity was evaluated by the histone H2AX phosphorylation level. RESULTS: Two novel mutations of MCM8, i.e., c.724T>C (p.C242R) and c.1334C>A (p.S445*), were identified in a 13‐year‐old girl with POI who exhibited disappeared bilateral ovaries and short stature (height standard difference score [HtSDS] = −3.05), and her sister (aged 6 years and 7 months) with progressive POI whose ovary size decreased from normal to unclear and height growth gradually slowed. In the functional experiments, compared with the wild‐type, HeLa cells overexpressing mutant p.C242R and p.S445* showed a higher sensitivity to MMC. Furthermore, the mutant p.S445* has a more deleterious effect on DNA damage repair. CONCLUSION: Our results reveal that affected children with the novel pathogenetic mutations p.C242R and p.S445* in the MCM8 gene are characterized by POI, short stature, cancer susceptibility, and genomic instability.