title: Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency.
abstract: BACKGROUND
  Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early menopause. Genes involved in essential steps in chromosome synapsis and recombination during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been shown to cause POI in animal models. We describe for the first time a homozygous mutation in SYCE1 in humans.
  
  
  OBJECTIVE
  To identify the genetic cause of POI in an Israeli Arab family with a consanguineous pedigree.
  
  
  METHODS
  A family-based genetic study conducted at a tertiary medical center.
  
  
  METHODS
  Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI. Genotyping was performed in the index patients, their parents, and four unaffected siblings.
  
  
  METHODS
  DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of the additional family members were determined by Sanger sequencing. Genotyping was also performed in 90 ethnically matched control individuals.
  
  
  RESULTS
  A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation. The mutation was not identified in the DNA samples from the 90 control subjects.
  
  
  CONCLUSIONS
  Given the known function of the SYCE1 gene, we suggest that the nonsense mutation identified accounts for the POI phenotype. These results highlight the importance of the synaptonemal complex and meiosis in ovarian function.
authors: The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes (L.d.V.), Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine (L.d.V., P.S.-Y., I.L., L.B.-V.), Tel Aviv University, Tel Aviv, Israel; Molecular Medicine Laboratory (D.M.B., S.T.), Rambam Health Care Campus, Haifa, Israel; Raphael Recanati Genetic Institute (D.M.B., L.B.-V.), Rabin Medical Center, Petach Tikva, Israel; Felsenstein Medical Research Center (P.S.-Y., I.L.), Petach Tikva, Israel; and Pediatric Genetics (L.B.-V.), Schneider Children's Medical Center of Israel, Petach Tikva; Israel.
authors: Liat
authors: L
authors: de Vries
authors: Doron M
authors: DM
authors: Behar
authors: Pola
authors: P
authors: Smirin-Yosef
authors: Irina
authors: I
authors: Lagovsky
authors: Shay
authors: S
authors: Tzur
authors: Lina
authors: L
authors: Basel-Vanagaite
mesh_terms: D000293:Adolescent; D000818:Animals; D018912:Arabs / Q000235:genetics*; D018389:Codon, Nonsense; D003241:Consanguinity; D004268:DNA-Binding Proteins; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008297:Male; D008594:Menopause, Premature / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D009866:Oogenesis / Q000235:genetics*; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011627:Puberty / Q000235:genetics; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C504910:SYCE1 protein, mouse; C489753:SYCP1 protein, human