• PMID: 25064402
• Gene Name: SOX3
• Condition: Idiopathic hypogonadotropic hypogonadism (IHH)
• Association: 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 clini
• Population size: 58
• Population details: 58 (58 patients with isolated HH (IHH), combined pituitary hormone deficiency (CPHD), and syndromic HH)
• Sex: Male, Female
• Infertility type: Male infertility, Female infertility
• Associated genes: FGFR1, SOX3, WDR11
• Other associated phenotypes: Idiopathic hypogonadotropic hypogonadism (IHH)

Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism

Izumi Y, Suzuki E, Kanzaki S, Yatsuga S, Kinjo S, Igarashi M, Maruyama T, Sano S, Horikawa R, Sato N, Nakabayashi K, Hata K, Umezawa A, Ogata T, Yoshimura Y, Fukami M.

OBJECTIVE: To clarify the molecular basis of hypogonadotropic hypogonadism (HH). DESIGN: 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. SETTING: Research institute. PATIENT(S): Fifty-eight patients with isolated HH (IHH), combined pituitary hormone deficiency (CPHD), and syndromic HH. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Frequency and character of molecular abnormalities. RESULT(S): 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. CONCLUSION(S): 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. CI - Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. FAU - Izumi, Yoko AU - Izumi Y AD - 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. FAU - Suzuki, Erina AU - Suzuki E AD - Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. FAU - Kanzaki, Susumu AU - Kanzaki S AD - Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori, Japan. FAU - Yatsuga, Shuichi AU - Yatsuga S AD - Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan. FAU - Kinjo, Saori AU - Kinjo S AD - Department of Pediatrics, Okinawa Chubu Hospital, Okinawa, Japan. FAU - Igarashi, Maki AU - Igarashi M AD - Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. FAU - Maruyama, Tetsuo AU - Maruyama T AD - Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan. FAU - Sano, Shinichiro AU - Sano S AD - Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. FAU - Horikawa, Reiko AU - Horikawa R AD - Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan. FAU - Sato, Naoko AU - Sato N AD - Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. FAU - Nakabayashi, Kazuhiko AU - Nakabayashi K AD - Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan. FAU - Hata, Kenichiro AU - Hata K AD - Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan. FAU - Umezawa, Akihiro AU - Umezawa A AD - Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan. FAU - Ogata, Tsutomu AU - Ogata T AD - Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. FAU - Yoshimura, Yasunori AU - Yoshimura Y AD - Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.