MCM9 Mutations Are Associated with Ovarian Failure, Short Stature, and Chromosomal Instability

Abstract

Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132(∗)) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature.

Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair

“…1000) and thus processes that affect the size of the oocyte pool will affect timing of menopause. Recent studies have shown that recessive mutations in both MCM8 and MCM9 results in genomic instability, caused by a deficiency in double strand break repair, which has a devastating effect on the oocyte pool, causing POI 10,30 . MCM8 is one of the genes highlighted in our study (signal #41) and a further 12 are also involved in homologous recombination repair, including two which are specific for meiotic repair (MSH5 and DMC1 (DNA meiotic recombinase 1)).…”

Genetics of primary ovarian insufficiency

“…SNP analysis and WES revealed several autosomal-recessive variants causing genomic-instability and association with hypergonadotropic hypogonadism (40,41,161).…”

“…The analysis of a few cohorts of 46,XX POI patients by means of high throughput techniques, such as comparative genomic hybridization array (array-CGH) and SNP array, has led to the identification of CNVs affecting several X-linked and autosomal loci with a possible role in female fertility (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Similarly, the recent application of whole-exome sequencing (WES) to a few POI multigenerational familial cases has succeeded in revealing rare single nucleotide variants affecting genes implicated in ovarian function (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). As already reported in other complex diseases characterized by a great genetic heterogeneity, it is likely that patients with POI may harbor multiple genetic variants.…”

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

“…The XRCC4 gene encodes a protein that functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DSB. In addition, recessive missense mutations in the homologous DNA repair enzyme MCM9 lead to a genomic instability syndrome associated with hypergonadotropic hypogonadism and short stature, much like the XRCC4 phenotype [155]. Gonadal failure appears to be a consistent finding in a number of these DNA damage repair syndromes.…”