Liping Wang1,2, Weisheng Lin3, Xiaohong Li1,2, Lijuan Zhang3, Kai Wang3, Xiaoli Cui3, Shanmei Tang3, Guangguang Fang4,5, Yan Tan4,5, Xuelai Wang6, Chuan Chen3, Chuanchun Yang3, Huiru Tang1,2. 1. Peking University Shenzhen Hospital. 2. Shenzhen Key Laboratory of Gynecological Diagnostic Technology Research. 3. CheerLand Precision Biomed Co., Ltd. 4. Shenzhen Dapeng New District Maternity & Child Health Hospital Department of Gynecology. 5. Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China. 6. Li Ka Shing Faculty of Medicine, School of Biomedical Science, the University of Hong Kong, Hong Kong.
Abstract
RATIONALE: This study aimed to investigate the genetic mutation characteristics of congenital idiopathic hypogonadotropic hypogonadism (IHH) through the clinical features and genetic analysis of 2 patients with IHH in 1 pedigree. PATIENT CONCERNS: A 23-year-old girl presented with primary amenorrhea, sparse pubic hair, lack of breast development, and delayed sexual development. DIAGNOSES: Combined with the clinical characteristics, auxiliary examinations, and molecular genetic analysis, the patient was diagnosed as IHH. INTERVENTIONS: Whole exome and Sanger sequencing were performed to validate the mutation in family members. OUTCOMES: A novel homozygous missense mutation c.521A > G (p.Q174R) in the GNRHR gene was identified in the 2 affected sisters. Familial segregation showed that the homozygous variant was inherited from their parents respectively and the eldest sister was the carrier without correlative symptom. LESSONS: We reported a novel GNRHR mutation in a pedigree with congenital idiopathic hypogonadotropic hypogonadism. Glutamine at amino acid position 174 was highly conserved among various species. The molecular structure of GNRHR protein showed that p.Q174R mutation brought in a new stable hydrogen bond between position 174 and 215, may impede conformational mobility of the TMD4 and TMD5. It suggests that the missense mutation c.521A > G related to congenital idiopathic hypogonadotropic hypogonadism was probably a causative factor for both sisters. Through high-throughput sequencing and experimental verification, we had basically determined the patient's pathogenic mutation and inheritance, which could better guide doctors for treatment.
RATIONALE: This study aimed to investigate the genetic mutation characteristics of congenital idiopathic hypogonadotropic hypogonadism (IHH) through the clinical features and genetic analysis of 2 patients with IHH in 1 pedigree. PATIENT CONCERNS: A 23-year-old girl presented with primary amenorrhea, sparse pubic hair, lack of breast development, and delayed sexual development. DIAGNOSES: Combined with the clinical characteristics, auxiliary examinations, and molecular genetic analysis, the patient was diagnosed as IHH. INTERVENTIONS: Whole exome and Sanger sequencing were performed to validate the mutation in family members. OUTCOMES: A novel homozygous missense mutation c.521A > G (p.Q174R) in the GNRHR gene was identified in the 2 affected sisters. Familial segregation showed that the homozygous variant was inherited from their parents respectively and the eldest sister was the carrier without correlative symptom. LESSONS: We reported a novel GNRHR mutation in a pedigree with congenital idiopathic hypogonadotropic hypogonadism. Glutamine at amino acid position 174 was highly conserved among various species. The molecular structure of GNRHR protein showed that p.Q174R mutation brought in a new stable hydrogen bond between position 174 and 215, may impede conformational mobility of the TMD4 and TMD5. It suggests that the missense mutation c.521A > G related to congenital idiopathic hypogonadotropic hypogonadism was probably a causative factor for both sisters. Through high-throughput sequencing and experimental verification, we had basically determined the patient's pathogenic mutation and inheritance, which could better guide doctors for treatment.
Authors: F Cioppi; A Riera-Escamilla; A Manilall; E Guarducci; T Todisco; G Corona; F Colombo; M Bonomi; C A Flanagan; C Krausz Journal: Andrology Date: 2018-12-21 Impact factor: 3.842
Authors: Elena Gianetti; Janet E Hall; Margaret G Au; Ursula B Kaiser; Richard Quinton; Jane A Stewart; Daniel L Metzger; Nelly Pitteloud; Veronica Mericq; Paulina M Merino; Lynne L Levitsky; Louise Izatt; Mariarosaria Lang-Muritano; Victor Y Fujimoto; Robert G Dluhy; Matthew L Chase; William F Crowley; Lacey Plummer; Stephanie B Seminara Journal: J Clin Endocrinol Metab Date: 2012-06-28 Impact factor: 5.958
Authors: F P Pralong; F Gomez; E Castillo; S Cotecchia; L Abuin; M L Aubert; L Portmann; R C Gaillard Journal: J Clin Endocrinol Metab Date: 1999-10 Impact factor: 5.958