Yoko Izumi1, Erina Suzuki2, Susumu Kanzaki3, Shuichi Yatsuga4, Saori Kinjo5, Maki Igarashi2, Tetsuo Maruyama6, Shinichiro Sano2, Reiko Horikawa7, Naoko Sato2, Kazuhiko Nakabayashi8, Kenichiro Hata8, Akihiro Umezawa9, Tsutomu Ogata10, Yasunori Yoshimura6, Maki Fukami11. 1. 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. 2. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. 3. Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori, Japan. 4. Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan. 5. Department of Pediatrics, Okinawa Chubu Hospital, Okinawa, Japan. 6. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan. 7. Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan. 8. Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan. 9. Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan. 10. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. 11. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address: fukami-m@ncchd.go.jp.
Abstract
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.
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 SOX3polyalanine 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.
Authors: Maria I Stamou; Harrison Brand; Mei Wang; Isaac Wong; Margaret F Lippincott; Lacey Plummer; William F Crowley; Michael Talkowski; Stephanie Seminara; Ravikumar Balasubramanian Journal: J Clin Endocrinol Metab Date: 2022-07-14 Impact factor: 6.134
Authors: Qing Fang; Akima S George; Michelle L Brinkmeier; Amanda H Mortensen; Peter Gergics; Leonard Y M Cheung; Alexandre Z Daly; Adnan Ajmal; María Ines Pérez Millán; A Bilge Ozel; Jacob O Kitzman; Ryan E Mills; Jun Z Li; Sally A Camper Journal: Endocr Rev Date: 2016-11-09 Impact factor: 19.871
Authors: Fernanda A Correa; Ericka B Trarbach; Cintia Tusset; Ana Claudia Latronico; Luciana R Montenegro; Luciani R Carvalho; Marcela M Franca; Aline P Otto; Everlayny F Costalonga; Vinicius N Brito; Ana Paula Abreu; Mirian Y Nishi; Alexander A L Jorge; Ivo J P Arnhold; Yisrael Sidis; Nelly Pitteloud; Berenice B Mendonca Journal: Endocr Connect Date: 2015-03-10 Impact factor: 3.335
Authors: Yeon-Joo Kim; Daniel Ps Osborn; Ji-Young Lee; Masatake Araki; Kimi Araki; Timothy Mohun; Johanna Känsäkoski; Nina Brandstack; Hyun-Taek Kim; Francesc Miralles; Cheol-Hee Kim; Nigel A Brown; Hyung-Goo Kim; Juan Pedro Martinez-Barbera; Paris Ataliotis; Taneli Raivio; Lawrence C Layman; Soo-Hyun Kim Journal: EMBO Rep Date: 2017-12-20 Impact factor: 8.807
Authors: Katie L Ayers; Aurore Bouty; Gorjana Robevska; Jocelyn A van den Bergen; Achmad Zulfa Juniarto; Nurin Aisyiyah Listyasari; Andrew H Sinclair; Sultana M H Faradz Journal: Hum Genomics Date: 2017-02-16 Impact factor: 4.639