Chengming Zhou1, Yonghua Niu2, Hao Xu2, Zongzhe Li1, Tao Wang2, Weimin Yang2, Shaogang Wang2, Dao Wen Wang1, Jihong Liu3. 1. Division of Cardiology, Department of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China. 2. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China. 3. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People's Republic of China. Electronic address: jhliu@tjh.tjmu.edu.cn.
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%), CHD7, FGFR1, 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 EGFR, ERBB4, PAX6, IGF1, SEMA4D, 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.
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%), CHD7, FGFR1, 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 EGFR, ERBB4, PAX6, IGF1, SEMA4D, 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.
Authors: Marina T DiStefano; Sarah E Hemphill; Andrea M Oza; Rebecca K Siegert; Andrew R Grant; Madeline Y Hughes; Brandon J Cushman; Hela Azaiez; Kevin T Booth; Alex Chapin; Hatice Duzkale; Tatsuo Matsunaga; Jun Shen; Wenying Zhang; Margaret Kenna; Lisa A Schimmenti; Mustafa Tekin; Heidi L Rehm; Ahmad N Abou Tayoun; Sami S Amr Journal: Genet Med Date: 2019-03-21 Impact factor: 8.822
Authors: Rossella Cannarella; Alyssa J J Paganoni; Stefania Cicolari; Roberto Oleari; Rosita A Condorelli; Sandro La Vignera; Anna Cariboni; Aldo E Calogero; Paolo Magni Journal: Int J Mol Sci Date: 2021-02-28 Impact factor: 5.923