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.

日本語要旨:

遺伝疾患パネルを用いて低ゴナドトロピン性性腺機能低下症58名の患者さんの遺伝子診断を行った結果、この疾患の原因と考えられる変異を二つの遺伝子で初めて同定した。