The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
Bibliographical noteFunding Information:
This work was supported by grants from Baillie Gifford ; Visually Impaired Children Taking Action (VICTA) ( www.victa.org.uk ); Microphthalmia, Anophthalmia and Coloboma Support (MACS) ( www.macs.org.uk ); HEIF (Health Innovation Fund, Oxford Brookes University); La Fondation de France (grant number 2015-00060235 , 2015); Fondation Maladies Rares and Retina France ; Fondazione Bambino Gesù (Vite Coraggiose); E-Rare (NSEuroNet); AIRC (the Italian Foundation for Cancer Research) ( IG 21614 ); the Italian Ministry of Health (Ricerca Corrente); and the National Heart, Lung, and Blood Institute ( R35 HL135742 ). French patients are part of the Rare Disease Cohort (RaDiCo)-AC-Oeil. RaDiCo is funded by the French National Research Agency under the specific program “Investments for the Future,” cohort grant agreement ANR-10-COHO-0003 . V.S. and J.S. were supported by UCB Celltech and the Duke Genome Sequencing Clinic grant. W.B.D. was supported by the US National Institutes of Health under the National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058721 . R.M.Y. and S.W.W. were supported by an MRC (Medical Research Council) Programme Grant ( MR/L003775/1 to S.W.W. and G. Gestri) and a Wellcome Trust Investigator Award ( 104682/Z/14/Z ). The human embryonic and fetal material was provided by the Joint MRC/Wellcome Trust (grant MR/R006237/1 ) Human Developmental Biology Resource ( www.hdbr.org ).
- Noonan syndrome