Skeletal ciliopathies

Gene: FUZ

Green List (high evidence)

Comment on list classification: There are 4 probands reported in literature with biallelic FUZ variants and features of skeletal ciliopathy, including limb shortening, short ribs, digit anomalies (polydactyly, syndactyly), cleft palate, and craniofacial abnormalities. In addition, Fuz-/- mice present with skeletal dysmorphologies (polydactyly on all limbs, malformed sternum, ribs, and long bones) stemming from disrupted ciliogenesis. Based on available evidence, FUZ can be upgraded to Green on this panel.

Created: 11 Nov 2026, 4:24 p.m. | Last Modified: 11 Nov 2026, 4:28 p.m.

Panel Version: 7.9

PMID: 41952398 Ogawa et al., 2026
Report of a Japanese male proband, homozygous for FUZ p.Arg234Trp (c.700C>T? not specified). He was prenatally diagnosed with cardiac anomalies and limb shortening. At birth, he presented with micrognathia, high‐arched palate, and polydactyly. He also experienced abdominal distension and vomiting since birth and was diagnosed with Hirschsprung disease. Head CT at 5  years of age was consistent with sagittal craniosynostosis. DD and epilepsy were noted in infancy. At time of report he is 12 yrs old and has severe ID and ASD. Head CT and MRI showed multiple cerebral malformations.

PMID: 38702430 Singh et al., 2024
Two FUZ variants: c.601G>A, p.Glu201Lys and c.625_636del, p.Val209_Leu212del, detected in biallelic state, in two Indian subjects exhibiting features of orofaciodigital syndrome: digital anomalies (polydactyly, syndactyly), orofacial cleft, short ribs and cardiac defects. Method: Exome seq.

PMID: 34719684 Barrell et al., 2022
Variant FUZ: c.851G>C, p.(Arg284Pro) was detected in a homozygous state in monozygotic twins presenting with craniosynostosis. Twin 1 presented with Metopic suture synostosis, Unilateral coronal synostosis, and Agenesis of the callosal body; Twin 2 had Metopic suture synostosis alone. Consanguineous, clinically unaffected parents. Seq method: WGS.
Functional studies: cultured primary osteoblasts and mouse embryonic fibroblasts (MEFs) from Fuz mutant mice. The FUZ p.(Arg284Pro) variant partially rescued the loss of primary cilia phenotype observed in mutant MEFs - thus, p.(Arg284Pro) variant does not result in a complete LoF in cilia formation. Loss of Fuz also resulted in increased osteoblastic mineralisation.

PMID: 29068549 Zhang et al., 2019
Reported a proband hom for FUZ c.98_111+9del variant, diagnosed with short-rib polydactyly syndrome. He presented with extreme polydactyly of all four limbs, and other skeletal features: long, narrow chest, moderately short ribs, short long bones, and hypoplastic tibiae. A hypoplastic left ventricle, ventricular septal defect, hypoplastic kidneys, midline facial cleft, thickened nuchal fold and dilated third ventricle were also noted. Variant is "predicted to lead to the deletion of five amino acids as well as the splice donor for exon 1" - no functional evidence given.

FUZ variants described above are either not reported or sufficiently rare in gnomAD v4.1.2, with no homozygotes reported.

Functional evidence:
PMID: 19767740 Gray et al., 2009, PMID: 19877275 Heydeck, Zeng, and Liu, 2009 - Fuz homozygous mutant mice (Fuz−/−) have markedly reduced numbers of primary cilia and shorter, structurally abnormal cilia in many tissues (neural tube, limb bud, craniofacial mesenchyme). Homozygous mutant mice displayed severe developmental defects, including craniofacial malformations, incompletely penetrant neural tube closure defects, consistent polydactyly on all limbs, malformed sternum, ribs, and long bones, as well as severely hypoplastic lungs and conotruncal defects.
PMID: 21935430 Zhang et al., 2011 - The Fuz-/- mice exhibited 'severe craniofacial deformities including anophthalmia, agenesis of the tongue and incisors, a hypoplastic mandible, cleft palate, ossification/skeletal defects and hyperplastic malformed Meckel's cartilage'.

FUZ is only associated with AD {Neural tube defects, susceptibility to}, OMIM:182940. There is no association in ClinGen, and FUZ-related orofaciodigital syndrome evidence is rated "Limited" in Gene2Phenotype. Resources accessed 6th Nov.

Created: 11 Nov 2026, 3:24 p.m. | Last Modified: 11 Nov 2026, 4:25 p.m.

Panel Version: 7.9

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
craniosynostosis, MONDO:0015469; orofaciodigital syndrome, MONDO:0015375

Publications

• 19767740
• 19877275
• 29068549
• 34719684
• 38702430
• 41952398