ClinVar

In the female proband from a large consanguineous 10-generation French Canadian family with anosmic hypogonadotropic hypogonadism (HH20; 615270) and cleft palate, previously reported by White et al. (1983) and in whom Tornberg et al. (2011) had identified missense mutations in the FGFR1 (R250Q; 136350.0025) and HS6ST1 (R296W; 604846.0002) genes, Miraoui et al. (2013) also identified heterozygosity for a c.323T-C transition in exon 4 of the FGF17 gene, resulting in an ile108-to-thr (I108T) substitution at a highly conserved residue in the FGF core domain. In addition, the proband was heterozygous and homozygous for 2 missense mutations in another FGF-network gene, FLRT3 (E97G, 604808.0001 and S144I, 604808.0002, respectively). Three other affected family members also carried mutations in the FGFR1, HS6ST1, and FLRT3 genes, and 4 unaffected family members carried 1 or 2 mutations in those genes, but none had a mutation in the FGF17 gene. The I108T mutation was not found in 155 controls or in the 1000 Genomes Project database. Analysis of physical interactions between the ligand-binding region of FGFR1 and FGF17 by surface-plasmon-resonance spectroscopy demonstrated that the I108T mutant was defective in FGFR1 activation compared to wildtype; in addition, the I108T mutant completely failed to activate the R250Q FGFR1 mutant, indicating that these 2 loss-of-function substitutions act in an additive manner.