A case report of congenital idiopathic hypogonadotropic hypogonadism caused by novel mutation of GNRHR gene

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.

Figure 1

Ultrasound image of patients: proband and her second eldest sister both appeared small uterus.

Figure 2

Mutation in sisters with IHH. (A) Sanger sequencing confirmed the mutation c.521A > G in GNRHR. The proband and her second eldest sister were homozygote, whereas her parents and eldest sister were heterozygote. The arrows indicated the position of mutation c.521A > G. (B) Pedigrees affected by IHH. The affected members (proband and her second eldest sister were indicated as black circles). IHH = idiopathic hypogonadotropic hypogonadism.

Figure 3

Structural model and conservation of mutation in GNRHR. (A) and (B) Three-dimensional structure of GNRHR, showing the protein domain. The positions of Ala163, Leu166, Ser168, Ala171, with olive color, were recorded in HGMD, located on the TMH4. The position of Q174 was on TMH4 too. (A) The structure of wild type, showing the Gln174 (Q174) with red color, connected with Phe170, Ala171, and Phe178 by hydrogen bond. (B) The structure of mutation, showing the Arg174 (R174) with red color, brought in a newly stable hydrogen bond between position Arg174 on TMH4 and Thr215 on TMH5. (C) The conservation of the p.Q174R and p.A171T in GNRHR was analyzed among various species. HGMD = Human Gene Mutation Database.