Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism

The study expands the mutation profile for isolated hypogonadotropic hypogonadism, and the new likely pathogenic genes identified in our study warrant further research for gonadotropin-releasing hormone neurons network.

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Volume 110, Issue 3, Pages 486–495.e5

Authors:

Chengming Zhou, M.D., Yonghua Niu, M.D., Hao Xu, M.D., Zongzhe Li, M.D., Tao Wang, M.D., Weimin Yang, M.D., Shaogang Wang, M.D., Dao Wen Wang, M.D., Ph.D., Jihong Liu, M.D., Ph.D

Abstract:

Objective

To investigate the mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism (IHH) and discover new pathogenic genes that cause IHH.

Design

A gene panel, including 31 known IHH genes and 52 candidate genes, was used to perform semiconductor next-generation sequencing.

Setting

University hospital.

Patients

One hundred thirty-eight sporadic male IHH patients and 10 IHH families; 100 healthy men with normal fertility served as control subjects.

Interventions(s)

None.

Main Outcome Measure(s)

Targeted next-generation sequencing, polymerase chain reaction and sequencing, pedigree analysis, and bioinformatics analysis.

Result(s)

Variants were distributed uniformly throughout 52 genes (52/83, 62.65%), including 16 (16/31, 51.61%) causal genes and 36 (36/52, 69.23%) candidate genes. Six new pathogenic variants and 52 likely pathogenic variants were identified in 16 genes known to cause nIHH/KS (normosmic IHH/Kallmann syndrome). In the 148 probands, PROKR2 (22/148, 14.86%), CHD7FGFR1, and KAL1 had high mutation rates, and 8.78% (13/148) of the patients carried at least two variants in known genes. In addition, variants were identified in 36 candidate genes, and EGFRERBB4PAX6IGF1SEMA4D, and SEMA7A should be prioritized for further research and genetic testing in IHH.

Conclusion(s)

The mutation frequency of IHH-causal genes in Chinese HAN males was different from the data reported in white populations. Oligogenic inheritance was a common phenomenon in IHH. Our study expands the mutation profile for IHH, and the new likely pathogenic genes identified in our study warrant further research in GnRH neuronal networks.


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Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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