Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism, "Beyond the Abstract," by Masafumi Kon and Maki Fukami

BERKELEY, CA ( - Hypogonadotropic hypogonadism (HH) is a clinically and genetically heterogeneous condition that occurs as an isolated hormone defect (isolated HH, IHH) or in combination with other pituitary hormone deficiencies (combined pituitary hormone deficiency, CPHD). In this study, Izumi et al. performed genome-wide copy-number analysis and systematic mutation screening of 29 known causative genes for 58 Japanese patients with IHH or CPHD. They identified apparently pathogenic defects in 14 of 58 patients. Pathogenic mutations frequently affected FGFR1 and CHD7. As rare genetic abnormalities, the authors identified submicroscopic deletion encompassing FGFR1, polyalanine deletion in SOX3, and a novel splice mutation in WDR11. Clinical analysis of the mutation-positive patients broadened the phenotypic spectrum of polyalanine deletions in SOX3 and mutations in WDR11 to include IHH and CPHD, respectively. This study provided novel information on the genetic basis and phenotypic variation of HH.

HH is a clinically important condition in the field of pediatric urology, mainly because it can lead to genital abnormalities in male patients. Indeed, three cases reported by Izumi et al. manifested genital abnormalities. It is known that the prevalence of HH is significantly higher in males than in females, reflecting the presence of disease-causing mutations in X-linked genes such as KAL1 and SOX3. Molecular analyses would help early diagnosis of HH. Furthermore, identification of the genetic causes of this condition is helpful in predicting the disease outcomes and possible complications of mutation-positive patients.

Importantly, this paper showed that submicroscopic copy-number abnormalities and mutations in known causative genes play relatively minor roles in the etiology of HH. Actually, pathogenic defects were identified only in ~25% of the patients. Thus, further studies, such as whole exome sequencing of the mutation-negative patients, are necessary to clarify the molecular basis of HH.

Written by:
Masafumi Kon,1, 2 and Maki Fukami1 as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

1Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
2Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

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

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