title: Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism.
abstract: OBJECTIVE
  To clarify the molecular basis of hypogonadotropic hypogonadism (HH).
  
  
  METHODS
  Genome-wide copy number analysis by array-based comparative genomic hybridization and systematic mutation screening of 29 known causative genes by next-generation sequencing, followed by in silico functional assessment and messenger RNA/DNA analyses of the mutants/variants.
  
  
  METHODS
  Research institute.
  
  
  METHODS
  Fifty-eight patients with isolated HH (IHH), combined pituitary hormone deficiency (CPHD), and syndromic HH.
  
  
  METHODS
  None.
  
  
  METHODS
  Frequency and character of molecular abnormalities.
  
  
  RESULTS
  Pathogenic defects were identified in 14 patients with various types of HH, although oligogenicity was not evident in this patient group. As rare abnormalities, we identified a submicroscopic deletion involving FGFR1 and an SOX3 polyalanine deletion in patients with IHH, and a WDR11 splice site mutation in a patient with CPHD. No disease-associated polymorphism was detected in the 58 patients.
  
  
  CONCLUSIONS
  The present study provides further evidence that mutations and deletions in the known causative genes play a relatively minor role in the etiology of HH and that submicroscopic rearrangements encompassing FGFR1 can lead to IHH as a sole recognizable clinical feature. Furthermore, the results indicate for the first time that polyalanine deletions in SOX3 and mutations in WDR11 constitute rare genetic causes of IHH and CPHD, respectively.
authors: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors: Yoko
authors: Y
authors: Izumi
authors: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Erina
authors: E
authors: Suzuki
authors: Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori, Japan.
authors: Susumu
authors: S
authors: Kanzaki
authors: Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.
authors: Shuichi
authors: S
authors: Yatsuga
authors: Department of Pediatrics, Okinawa Chubu Hospital, Okinawa, Japan.
authors: Saori
authors: S
authors: Kinjo
authors: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Maki
authors: M
authors: Igarashi
authors: Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors: Tetsuo
authors: T
authors: Maruyama
authors: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Shinichiro
authors: S
authors: Sano
authors: Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan.
authors: Reiko
authors: R
authors: Horikawa
authors: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Naoko
authors: N
authors: Sato
authors: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Kazuhiko
authors: K
authors: Nakabayashi
authors: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Kenichiro
authors: K
authors: Hata
authors: Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Akihiro
authors: A
authors: Umezawa
authors: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Tsutomu
authors: T
authors: Ogata
authors: Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
authors: Yasunori
authors: Y
authors: Yoshimura
authors: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address: fukami-m@ncchd.go.jp.
authors: Maki
authors: M
authors: Fukami
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D055106:Genome-Wide Association Study; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis / Q000235:genetics*; D007018:Hypopituitarism / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D012307:Risk Factors; D055748:SOXB1 Transcription Factors / Q000235:genetics; D055815:Young Adult; D000092468:Bromodomain Containing Proteins
chemical_list: D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D055748:SOXB1 Transcription Factors; C527785:SOX3 protein, human; C435527:WDR11 protein, human; D000092468:Bromodomain Containing Proteins; C496348:FGFR1 protein, human
keywords: FGFR1; SOX3; WDR11; genomic rearrangements; gonadotropin deficiency; mutation