FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including , , and . The aim of this study was to investigate the genotypic and phenotypic spectra of these genes in a large cohort of Chinese patients with IHH.
A total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing.
Four heterozygous variants (p.S157I, p.R83Q, p.P188L and p.N355I) were found in six patients. Cryptorchidism, dental agenesis, syndactyly and blue colour blindness were commonly observed in patients with mutations. Six heterozygous variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients. Segregation analysis indicated that 100% (5/5) of probands inherited the variants from their unaffected parents, and oligogenicity was found in 4/7 patients. One rare variant (p.T68S) was found in a female patient with Kallmann syndrome who also carried a mutation.
Our study greatly enriched the genotypic and phenotypic spectra of , and in IHH. Mutations in alone seem sufficient to cause IHH in an autosomal dominant manner, whereas or mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes.

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