ORPHA: 2345; DO: 0080591;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.31 | Klippel-Feil syndrome 3, autosomal dominant | 613702 | 3 | GDF3 | 606522 |
A number sign (#) is used with this entry because Klippel-Feil syndrome-3 (KFS3) is caused by heterozygous mutation in the GDF3 gene (606522) on chromosome 12p13.
Klippel-Feil syndrome (KFS) is a congenital anomaly characterized by a defect in the formation or segmentation of the cervical vertebrae, resulting in a fused appearance. The clinical triad consists of short neck, low posterior hairline, and limited neck movement, although less than 50% of patients demonstrate all 3 clinical features (Tracy et al., 2004).
For a general description and a discussion of genetic heterogeneity of Klippel-Feil syndrome, see KFS1 (118100).
Ye et al. (2010) described a 3-generation North American family with a spectrum of ocular and skeletal phenotypes. The proband had unilateral iris, retinal coloboma, rudimentary 12th ribs, and mild scoliosis. Her mother and aunt had Klippel-Feil cervical fusion at C5-6 and C3-4, respectively, and her grandfather had lumbar and thoracic scoliosis.
Klippel-Feil syndrome-3 is an autosomal dominant disorder (Ye et al., 2010).
In a 3-generation North American family with Klippel-Feil syndrome, Ye et al. (2010) identified a heterozygous missense mutation (606522.0001) in the GDF3 gene that segregated with the skeletal phenotype in 4 family members.
By morpholino knockdown of dvr1, which is the GDF3/GDF1 (602880) zebrafish homolog, Ye et al. (2010) recapitulated ocular and skeletal phenotypes seen in human. Ocular features apparent at 48 hours postfertilization in zebrafish included coloboma and reduced ocular size. Histologic exam revealed consistent reductions in ocular, lenticular, and retinal size, that accord with the microphthalmia seen at earlier stages in live embryos. Skeletal defects ranged from mild to severe tail curvature and reduced tail length.
Tracy, M. R., Dormans, J. P., Kusumi, K. Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin. Orthop. Relat. Res. 424: 183-190, 2004. [PubMed: 15241163]
Ye, M., Berry-Wynne, K. M., Asai-Coakwell, M., Sundaresan, P., Footz, T., French, C. R., Abitbol, M., Fleisch, V. C., Corbett, N., Allison, W. T., Drummond, G., Walter, M. A., Underhill, T. M., Waskiewicz, A. J., Lehmann, O. J. Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum. Molec. Genet. 19: 287-298, 2010. [PubMed: 19864492] [Full Text: https://doi.org/10.1093/hmg/ddp496]