Novel FGF9 variant contributes to multiple synostoses syndrome 3

Abstract

Multiple synostoses syndromes (SYNS) are autosomal dominant syndromes characterized by multiple joint fusions commonly involving the carpal‐tarsal, interphalangeal, humeroradial, and cervical spine joints. They display genetic heterogeneity with pathogenic variants reported in four separate genes (NOG, GDF5, FGF9, and GDF6) defining four different SYNS forms. FGF9 variants have been reported in SYNS3, a SYNS with multiple synostoses, normal cognition, normal hearing, and craniosynostosis. Here, we report a novel FGF9 c.569G > C p.(Arg190Thr) variant identified by whole‐exome sequencing in a patient with multiple bony abnormalities. The patient initially presented with elbow instability and decreased range of motion. Imaging revealed bilateral radial head deformities, carpal‐tarsal fusions, brachydactyly, and osteoarthritis of the sacroiliac joints. In silico protein modeling of the identified FGF9 variant predicts decreased stability of ligand‐receptor binding supporting the pathogenicity of this finding. This finding expands the repertoire of FGF9 variants and phenotypic information reported for SYNS3 and suggest that genotype phenotype correlations due to localization seem less likely and more so due to the consequence of the pathogenic variant on the receptor. This is useful in the counseling in families as more de novo variants emerge.

FGF9 variant in 46,XY DSD patient suggests a role for dimerization in sex determination

“…Five FGF9 variants (R62G, S99N, N143Y, P189R, R190T) in humans cause multiple synostoses syndromes with or without craniosynostosis 18–22 . Unresolved is why humans and mice with D195N do not show synostosis.…”

“…The patient also presented with a small slightly dysplastic right kidney with normal renal function. Although no abnormal renal phenotypes have been reported in patients with FGF9 variants, 18–22 in mice FGF9 and FGF20 act redundantly and are crucial for kidney development 44 . One Fgf9 knockout allele on a Fgf20 null background leads to a reduction in nephron numbers and small dysplastic kidneys.…”

“…42 Five FGF9 variants (R62G, S99N, N143Y, P189R, R190T) in humans cause multiple synostoses syndromes with or without craniosynostosis. [18][19][20][21][22] Unresolved is why humans and mice with The patient did present with mild scoliosis, a phenotype seen occasionally in patients with FGFR2c mutations. 43 The patient also presented with a small slightly dysplastic right kidney with normal renal function.…”

“…43 The patient also presented with a small slightly dysplastic right kidney with normal renal function. Although no abnormal renal phenotypes have been reported in patients with FGF9 variants, [18][19][20][21][22] in mice FGF9 and FGF20 act redundantly and are crucial for kidney development. 44 One…”

“…2,3,17 Clinically, the only phenotype associated with FGF9 variants is multiple synostoses syndrome (SYNS3 OMIM# 612961) with or without craniosynostosis, an autosomal dominant skeletal disorder caused by an overgrowth of bone at the joints or the cranial sutures. [18][19][20][21][22] To date, five heterozygous missense variants in FGF9 (NM_002010.2) were found in SYNS3 patients, c.184A > G;p.(Arg62Gly) (R62G), c.296G > A;p.(Ser99Asn) (S99N), c.427A > T;p.(Asn143Tyr) (N143Y), c.566C > G;p.(Pro19Arg) (P189R) and c.569G > C;p.(Arg190Thr) (R190T). [18][19][20][21][22] The mouse models Fgf9 N143T and Fgf9 S99N show partial XY sex reversal 23 , suggesting that pathogenic FGF9 variants in humans might also contribute to gonadal defects.…”