A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency

Clin Genet. 2016 May;89(5):603-7. doi: 10.1111/cge.12736. Epub 2016 Feb 10.


Primary ovarian insufficiency (POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole-exome sequencing of the two patients and a non-affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c.1483G>T [p.E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum.

Keywords: MCM9; exome sequencing; infertility; primary ovarian insufficiency; reproductive medicine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Codon, Nonsense*
  • Consanguinity
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • INDEL Mutation
  • Male
  • Minichromosome Maintenance Proteins / genetics*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Primary Ovarian Insufficiency / genetics*


  • Codon, Nonsense
  • MCM9 protein, human
  • Minichromosome Maintenance Proteins