Skeletal dysplasia

Gene: FGF4

Green List (high evidence)

Comment on list classification: Promoting to amber with a recommendation of green rating following GMS review. 2 unrelated cases plus a supportive mouse model.

Created: 14 Jul 2025, 9:23 p.m. | Last Modified: 14 Jul 2025, 9:23 p.m.

Panel Version: 8.6

Associated with Short-rib thoracic dysplasia 22 without polydactyly, OMIM:621260 (AR)

PMID: 40259859 - Watts et al 2025 report 2 unrelated families (1 in the 100,000 Genomes project) with a clinical diagnosis of thoracic dystrophy with associated respiratory insufficiency.

Family 1 - 2 affected boys clinically suspected to have Jeune syndrome, and 3 unaffected children born to healthy consanguineous 2nd cousin parents. Both affected individuals had narrow/small thorax and short ribs (11 pairs). 2nd child died at 3  months from respiratory infection. Both affected children were homozygous for a missense variant in FGF4 (c.256C>T p.(Leu86Phe)). Parents are confirmed carriers and 2 of the 3 unaffected siblings do not carry the variant.

Family 2 - 1 male with a chest shape suggesting thoracic dystrophy and a clinical suspicion of Jeune syndrome. A biallelic missense variant in FGF4 NM_002007.4:c.611C>A p.(Pro204His) was identified. Parents were both heterozygous carriers.

The variants are absent from gnomAD and UK Biobank and are predicted to be damaging by multiple in silico tools.

PMID: 33210601 - Anderson et al 2020 - Mouse mutants lacking Fgf4 Fgf4 show a variety of segmentation defects in the cervical and thoracic vertebrae with 100% penetrance.
Sources: Literature

Created: 14 Jul 2025, 9:22 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Short-rib thoracic dysplasia 22 without polydactyly, OMIM:621260; Jeune syndrome, MONDO:0018770

Publications

• 40259859
• 33210601