Skeletal dysplasia

Gene: FGF9

Green List (high evidence)

Thuresson et al. (2021) identified a de novo heterozygous missense variant in FGF9 (Pro189Arg) in 16‐year old boy with multiple synostoses syndrome. Functional studies showed this variant impairs FGF9 homodimerization, but not FGFR3c binding.

Wu et al. (2009) identified a heterozygous missense variant in FGF9 (S99N) in 5-generation Chinese family with AD multiple synostoses syndrome. Variant segregated with disease and was not found in 250 unrelated ethnically matched controls. Biochemical analysis reveals that S99N mutation in FGF9 leads to significantly impaired FGF signaling, as evidenced by diminished activity of Erk1/2 pathway and decreased beta-catenin and c-Myc expression when compared with wild-type FGF9.

Rodriguez-Zabala et al. (2017) identified a heterozygous missense variant in FGF9 (R62G) in a Spanish father and son with multiple synostoses syndrome and craniosynostosis. Variant segregated with disease in the family and was not found in 150 Spanish controls or in the gnomAD database. The mutation appeared to have arisen de novo in the father, as it was not detected in the biologically confirmed unaffected paternal grandparents. Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding.

Sentchordi-Montané et al. (2021) identified a heterozygous missense variant in FGF9 (Asn143Tyr) in a young girl with a multiple joint synostosis.

Created: 1 Feb 2021, 9:13 a.m. | Last Modified: 1 Feb 2021, 9:13 a.m.

Panel Version: 2.80

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Multiple synostoses syndrome 3, OMIM # 612961

Publications

• 33140402
• 28730625
• 19589401
• 33174625

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Defects in joint formation and synostoses gp of SD. Two cases reported, one with multiple synostoses syndrome and one with sagittal suture synostosis. Missense variants with no functional studies. (Wu et al 2009, Rodriguez-Zabala et al 2017). Dominant mouse mutant has elbow knee synostosis - ? Amber; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Multiple synostoses syndrome type 3 612961

Publications

• 19589401

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:08 a.m. | Last Modified: 11 Oct 2023, 11:08 a.m.

Panel Version: 4.20

Comment on list classification: Promoting this gene from red to amber but with a recommendation for GREEN rating following GMS review as 4 unrelated cases with variants in FGF9 and a phenotype of multiple synostoses syndrome.

Created: 30 May 2023, 12:26 a.m. | Last Modified: 30 May 2023, 12:26 a.m.

Panel Version: 4.8

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: FGF9; Initial rating suggestion: amber

Created: 6 Mar 2019, 11:36 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Red List (low evidence)

Comment on mode of inheritance: from publication PMID 19589401

Created: 10 Apr 2017, 12:56 p.m.

Single variant c.296G>A p.(Ser99 Asn) reported in 12 affected members of a 5-generation Chinese family with autosomal dominant multiple synostoses syndrome. Supporting functional data provided.
Probable G2P association

Created: 10 Apr 2017, 12:52 p.m.

Listed as associated with Skeletal Dysplasia by Gene Advisor (June 2016), Steve Abbs

Created: 27 Jul 2016, 9:35 a.m.

Comment on list classification: Used diagnostically by Ana Beleza (Guy's and St Thomas' NHS Foundation Trust)

Created: 21 Jun 2016, 12:48 p.m.

Publications

• 19589401

Green List (high evidence)

Tier 2

Created: 17 Jun 2016, 8:04 a.m.

Mode of inheritance
Unknown

Phenotypes
Multiple synostoses syndrome 3 612961

Variants in this GENE are reported as part of current diagnostic practice