A novel heterozygous variant in FGF9 associated with previously unreported features of multiple synostosis syndrome 3

Abstract

Human multiple synostoses syndrome 3 is an autosomal dominant disorder caused by pathogenic variants in FGF9. Only two variants have been described in FGF9 in humans so far, and one in mice. Here we report a novel missense variant c.566C > G, p.(Pro189Arg) in FGF9. Functional studies showed this variant impairs FGF9 homodimerization, but not FGFR3c binding. We also review the findings of cases reported previously and report on additional features not described previously.

Keywords: FGF9; SYNS; fusion of interphalangeal joints; multiple synostosis syndrome.

FIGURE 1

Radiographs showing the present patient with SYNS3 and a missense variant in FGF9. (A) Radial head dislocation of the elbow; (B) Normal elbow; (C) Synostosis of the interphalangeal joints of the thumb; (D) Normal thumb; (E) Suspected calcaneonavicular coalition of the feet; (F) Normal foot; (G) Synostosis of dig I and of the distal interphalangeal joints of dig II‐V of the feet; (H) Synostosis of the dorsal structures of the lumbar spine; (I, K) Well defined vertebrae and intervertebral joints of the lumbar spine and (J) Reduced height of the disc L3‐L4 and L4‐L5

FIGURE 2

FGF9 homodimerization and quantification of FGF9:FGFR3 binding. (A) Quantification of FGF9 homodimerization events detected using PLA. All values were normalised to wildtype (WT) set at 100. (B‐C) Representative images of intercellular FGF9:FGF9 homodimerization of WT, P189R:P189R (P189R) and R62G:R62G (R62G)‐FGF9 variants. E, Quantification of FGF9 binding to FGFR3c events detected using PLA signals. All values were normalised to WT set at 100. (F‐H) Representative images of intercellular FGF9: FGFR3c interactions of WT, P189R and R62G‐FGF9 variants. Graphs represent the mean +/− SEM of n = 3 biological repeats (black dots),*p < 0.05 and **p < 0.01 using one way ANOVA with Dunnett's multiple comparison test. Representative images use a white scale bar 10um, DAPI‐cyan, PLA signals‐magenta dots [Colour figure can be viewed at wileyonlinelibrary.com]