Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Neurodevelopmental, jaw, eye, and digital syndrome (MONDO:0030057) is a rare autosomal dominant condition characterized by hydrocephalus, severe developmental delay, mandibular hypoplasia, eye anomalies, and digital malformations. FBXW11 (HGNC:13607) encodes an F-box/WD40 protein integral to SCF ubiquitin ligase–mediated regulation of developmental signaling pathways.
A multi-patient cohort described seven unrelated probands harboring de novo missense FBXW11 variants absent from population databases, all presenting with overlapping neurodevelopmental, jaw, eye, and digit anomalies (PMID:31402090). Variants cluster on surface loops of the WD40 substrate-binding domain, including c.1543C>T (p.Arg515Cys) and c.1403G>A (p.Arg468Gln), predicted to destabilize protein–substrate interactions.
A second case report identified an additional de novo NM_001378974.1:c.1220A>T (p.Lys407Ile) variant in the conserved WD4 repeat in an 8-year-old with hydrocephalus, major developmental delay, mandibular hypoplasia, and eye/digital anomalies, expanding the variant and phenotypic spectrum to eight probands (PMID:40178747).
All pathogenic FBXW11 variants arose de novo, consistent with autosomal dominant inheritance and absence of affected relatives. No familial segregation has been observed.
The variant spectrum in NEDJED is exclusively missense, with nine unique substitutions reported to date. No recurrent or founder alleles have been described.
Functional studies demonstrate FBXW11 expression in human embryonic brain, eye, mandibular processes, and limb buds, and zebrafish knockdown of fbxw11a/1b yields smaller, misshapen eyes, jaw defects, and pectoral fin anomalies recapitulating patient features (PMID:31402090). Structural modeling supports a haploinsufficiency or dominant-negative mechanism via impaired substrate binding.
No conflicting evidence has been reported.
Integration of genetic and experimental data supports a strong association between heterozygous FBXW11 missense variants and neurodevelopmental, jaw, eye, and digital syndrome. FBXW11 should be included in diagnostic gene panels for patients with overlapping neurodevelopmental, craniofacial, ocular, and digital anomalies.
Gene–Disease AssociationStrongEight unrelated probands with de novo FBXW11 missense variants from two independent studies, with consistent phenotype and functional concordance Genetic EvidenceStrong8 de novo missense variants in 8 probands with NEDJED; variant clustering in the WD40 domain supports pathogenicity Functional EvidenceModerateEmbryonic expression studies and zebrafish knockdown replicate key ocular, jaw, and digital defects |