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

Yoko Izumi, Erina Suzuki, Susumu Kanzaki, Shuichi Yatsuga, Saori Kinjo, Maki Igarashi, Tetsuo Maruyama, Shinichiro Sano, Reiko Horikawa, Naoko Sato, Kazuhiko Nakabayashi, Kenichiro Hata, Akihiro Umezawa, Tsutomu Ogata, Yasunori Yoshimura, Maki Fukami

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1130-1136.e3
JournalFertility and Sterility
Volume102
Issue number4
DOIs
Publication statusPublished - 2014 Oct 1

Fingerprint

Hypogonadism
Genome
Mutation
Comparative Genomic Hybridization
Sequence Deletion
Computer Simulation
Genes
Outcome Assessment (Health Care)
Messenger RNA
DNA
Combined Pituitary Hormone Deficiency

Keywords

  • FGFR1
  • genomic rearrangements
  • gonadotropin deficiency
  • mutation
  • SOX3
  • WDR11

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Reproductive Medicine
  • Medicine(all)

Cite this

Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism. / Izumi, Yoko; Suzuki, Erina; Kanzaki, Susumu; Yatsuga, Shuichi; Kinjo, Saori; Igarashi, Maki; Maruyama, Tetsuo; Sano, Shinichiro; Horikawa, Reiko; Sato, Naoko; Nakabayashi, Kazuhiko; Hata, Kenichiro; Umezawa, Akihiro; Ogata, Tsutomu; Yoshimura, Yasunori; Fukami, Maki.

In: Fertility and Sterility, Vol. 102, No. 4, 01.10.2014, p. 1130-1136.e3.

Research output: Contribution to journalArticle

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 2014, 'Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism', Fertility and Sterility, vol. 102, no. 4, pp. 1130-1136.e3. https://doi.org/10.1016/j.fertnstert.2014.06.017
Izumi, Yoko ; Suzuki, Erina ; Kanzaki, Susumu ; Yatsuga, Shuichi ; Kinjo, Saori ; Igarashi, Maki ; Maruyama, Tetsuo ; Sano, Shinichiro ; Horikawa, Reiko ; Sato, Naoko ; Nakabayashi, Kazuhiko ; Hata, Kenichiro ; Umezawa, Akihiro ; Ogata, Tsutomu ; Yoshimura, Yasunori ; Fukami, Maki. / Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism. In: Fertility and Sterility. 2014 ; Vol. 102, No. 4. pp. 1130-1136.e3.
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T1 - Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism

AU - Izumi, Yoko

AU - Suzuki, Erina

AU - Kanzaki, Susumu

AU - Yatsuga, Shuichi

AU - Kinjo, Saori

AU - Igarashi, Maki

AU - Maruyama, Tetsuo

AU - Sano, Shinichiro

AU - Horikawa, Reiko

AU - Sato, Naoko

AU - Nakabayashi, Kazuhiko

AU - Hata, Kenichiro

AU - Umezawa, Akihiro

AU - Ogata, Tsutomu

AU - Yoshimura, Yasunori

AU - Fukami, Maki

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

KW - FGFR1

KW - genomic rearrangements

KW - gonadotropin deficiency

KW - mutation

KW - SOX3

KW - WDR11

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