title: Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism.
abstract: BACKGROUND
  Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function.
  
  
  OBJECTIVE
  The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families.
  
  
  METHODS
  Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families.
  
  
  RESULTS
  Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs*4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance.
  
  
  CONCLUSIONS
  Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism.
authors.affiliation: Department of Molecular and Human Genetics (Y.B., T.Ga., M.M.A., E.K., D.P., J.R.L.), Baylor College of Medicine, Houston, Texas 77030; Department of Medicine, Division of Medical Genetics (S.G., H.U.G., S.B.P., M.L., T.W., M.-C.K.), University of Washington, Seattle, Washington 98195; Department of Pediatric Endocrinology and Diabetes (T.Gu., Z.A., S.T., A.Be.), Marmara University Hospital, Istanbul, Turkey 34899; Department of Pediatric Endocrinology (A.Ab., E.Bob., A.Bu.), Dokuz Eylül University Faculty of Medicine, Izmir, Turkey 35340; Department of Medical Genetics (G.Y.), Bezmialem University, Istanbul, Turkey 34093; Human Genome Sequencing Center (S.N.J., D.M., E.Boe., R.A.G.), Baylor College of Medicine, Houston, Texas 77030; Human Genetics Center (E.Boe.), University of Texas Health Science Center at Houston, Houston, Texas 77030; Department of Pediatrics (J.R.L.), Baylor College of Medicine, Houston, Texas 77030; and Texas Children's Hospital (J.R.L.), Houston, Texas 77030.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Bayram
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.forename: Tulay
authors.initials: T
authors.lastname: Guran
authors.forename: Ayhan
authors.initials: A
authors.lastname: Abaci
authors.forename: Gozde
authors.initials: G
authors.lastname: Yesil
authors.forename: Hilal Unal
authors.initials: HU
authors.lastname: Gulsuner
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Atay
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Pierce
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.forename: Ming
authors.initials: M
authors.lastname: Lee
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.forename: Ece
authors.initials: E
authors.lastname: Bober
authors.forename: Mehmed M
authors.initials: MM
authors.lastname: Atik
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
authors.forename: Atilla
authors.initials: A
authors.lastname: Buyukgebiz
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000293:Adolescent; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D059472:Exome; D005260:Female; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D009154:Mutation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C552401:SOHLH1 protein, human