title: MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.
abstract: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI).
  
  
  
  MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants.
  
  
  
  Academic research institution.
  
  
  
  All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels.
  
  
  
  None.
  
  
  
  We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging.
  
  
  
  MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway.
  
  
  
  We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors: Swapna
authors: S
authors: Desai
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors: Michelle
authors: M
authors: Wood-Trageser
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors: Jelena
authors: J
authors: Matic
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors: Jaqueline
authors: J
authors: Chipkin
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors: Huaiyang
authors: H
authors: Jiang
authors: AP-HP, IE3M, Hôpital Pitié-Salpêtrière, Department of Endocrinology and Reproductive Medicine and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares, ICAN, 75651 Paris, Cedex 13 France.
authors: Anne
authors: A
authors: Bachelot
authors: AP-HP, IE3M, Hôpital Pitié-Salpêtrière, Department of Endocrinology and Reproductive Medicine and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares, ICAN, 75651 Paris, Cedex 13 France.
authors: Jerome
authors: J
authors: Dulon
authors: San Raffaele Research Institute, Milano, 20132 Italy.
authors: Cinzia
authors: C
authors: Sala
authors: San Raffaele Research Institute, Milano, 20132 Italy.
authors: Caterina
authors: C
authors: Barbieri
authors: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo," University of Trieste, Trieste, 34137 Italy.
authors: Massimiliano
authors: M
authors: Cocca
authors: San Raffaele Research Institute, Milano, 20132 Italy.
authors: Daniela
authors: D
authors: Toniolo
authors: AP-HP, IE3M, Hôpital Pitié-Salpêtrière, Department of Endocrinology and Reproductive Medicine and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares, ICAN, 75651 Paris, Cedex 13 France.
authors: Philippe
authors: P
authors: Touraine
authors: Department of Endocrinology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
authors: Selma
authors: S
authors: Witchel
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.|Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and.|Department of Human Genetics, University of Pittsburgh, Pennsylvania 15261.
authors: Aleksandar
authors: A
authors: Rajkovic
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D006801:Humans; D064110:Minichromosome Maintenance Proteins / Q000235:genetics*; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C471623:MCM8 protein, human; C501931:MCM9 protein, human; D064110:Minichromosome Maintenance Proteins