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

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.