Exp Clin Endocrinol Diabetes 2021; 129(06): 457-463
DOI: 10.1055/a-1151-4800
Article

Functional Characteristics of Novel FGFR1 Mutations in Patients with Isolated Gonadotropin-Releasing Hormone Deficiency

1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
,
Arum Oh
1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
,
Yena Lee
1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
,
Gu-Hwan Kim
2  Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
,
Han-Wook Yoo
1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
› Author Affiliations
Funding: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1D1A1B03029638) and with a grant (2019-481) from the Asan Medical Center Children's Hospital, Seoul, Korea.

Abstract

Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) has a wide phenotypic spectrum including Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). FGFR1 mutations have been identified in 3–10% of patients with KS or nIHH. This study was performed to investigate clinical phenotypes and functional characteristics of FGFR1 mutations in patients with IGD.

Methods This study included 8 patients (from 7 families) with FGFR1 mutations identified by targeted gene panel sequencing or whole exome sequencing (WES). The impact of the identified mutations on FGFR1 function was assessed using in vitro studies.

Results Seven heterozygous mutations in FGFR1 were identified in 8 patients from 7 independent families. The patients exhibited a wide spectrum of pubertal development, including anosmia in a prepubertal boy (n=1), delayed puberty (n=2), nIHH (n=3), and KS (n=2). Four of the mutations were classified as likely pathogenic, and the other three were variants of uncertain significance. FGF8-FGFR1 signaling activities for the novel FGFR1 variants (p.Y339H, p.S681I, and p.N185Kfs*16) were reduced by in vitro functional assay, indicating loss-of-function mutations.

Conclusions This study identified seven rare sequence variants in FGFR1 in patients with KS and nIHH. Probands with an FGFR1 mutations displayed a wide phenotypic spectrum ranging from KS to anosmia. A prepubertal male with anosmia should be followed up to assess pubertal development because they can manifest hypogonadotropic hypogonadism after puberty. These results expand the phenotypic spectrum of FGFR1 mutations and suggest a broader biologic role of FGFR1 in reproduction.



Publication History

Received: 12 February 2020
Received: 26 March 2020

Accepted: 02 April 2020

Publication Date:
02 June 2020 (online)

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