Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 498497, 93271; DO: 0110090;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p24.1 | Short-rib thoracic dysplasia 7 with or without polydactyly | 614091 | Autosomal recessive | 3 | WDR35 | 613602 |
A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-7 with or without polydactyly (SRTD7) is caused by homozygous or compound heterozygous mutation in the WDR35 gene (613602) on chromosome 2p24. There is also evidence of digenic inheritance.
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013).
There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330).
For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Kannu et al. (2007) reported a New Zealand family of Maori descent with 2 consecutive pregnancies complicated by an 'unclassifiable' short rib polydactyly syndrome that was most similar to SRPS type III (SRTD3; 613091) but was associated with acromesomelic hypomineralization and campomelia. The sibs exhibited several additional hallmarks of ciliopathic disease, including polysyndactyly, laterality defects, and cystic kidneys.
Mill et al. (2011) reported a fetus with an SRPS phenotype associated with extreme micromelia, postaxial polydactyly, and facial abnormalities.
Caparros-Martin et al. (2015) studied 5 patients from 3 unrelated families with short ribs, mesomelic shortening of limbs, and tooth and nail dysplasia, who exhibited features characteristic of EVC, including postaxial polydactyly of all limbs, absence of upper mucobuccal fold, and multiple oral frenula, as well as some findings more commonly seen in CED, including dolichocephaly in 2 patients and renal failure and hepatic failure in 2 other patients. However, the authors noted that these patients did not show the distinctive facial appearance of CED, and designated the clinical diagnosis as 'a new form of EVC.'
Duran et al. (2017) reported 3 sibs and an unrelated female infant with an unusual form of SRPS that included bent ribs and long bones, and undermineralization of the calvarium. The sibs exhibited short ribs, short limbs, bilateral postaxial polydactyly of the hands and feet with aphalangia of the hands, and bending of humeri, radii, and ulnae. Other significant findings included echogenic kidneys and bowel, scalp edema,and cystic hygroma. The unrelated female infant was diagnosed with SRPS prenatally and died 1 week after birth. Radiographic findings included micromelia, small thorax with short and bent ribs, pelvis with flat acetabular roofs, and bending of distal long bones. Other features included skin edema and ascites. She did not have polydactyly.
In 2 sibs with a severe form of short-rib thoracic dysplasia, previously reported by Kannu et al. (2007), Mill et al. (2011) mapped the disease locus to a 5.5-Mb region on chromosome 2p24.
In 2 sibs with short-rib thoracic dysplasia-7, previously reported by Kannu et al. (2007), Mill et al. (2011) identified a homozygous deletion mutation in the WDR35 gene (613602.0005). In an unrelated fetus with SRTD7, they identified compound heterozygosity for a nonsense and a missense mutation in the WDR35 gene (613602.0006-613602.0007).
In 2 brothers, born of consanguineous parents from Reunion Island, with a clinical diagnosis of EVC but without mutation in the EVC (604831) and EVC2 (607261) genes, Caparros-Martin et al. (2015) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the WDR35 gene (613602.0011). Their first-cousin parents were heterozygous for the mutation, which was not found in an unaffected brother or in public variant databases. Screening of the WDR35 gene in a panel of 10 probands, who were diagnosed with EVC but in whom no mutation in the EVC and EVC2 genes had been found, identified 2 more probands with biallelic mutations in WDR35, including an Italian boy with an affected sister, and an Egyptian girl. Functional analysis revealed that all 4 of the WDR35 variants affected splicing.
In 3 sibs and an unrelated female infant with an unusual form of SRPS involving bent ribs and long bones as well as undermineralization of the skull, Duran et al. (2017) performed exome analysis and in each family identified compound heterozygosity for a missense mutation and a truncating mutation in the WDR35 gene (see, e.g., 613602.0013 and 613602.0014). Noting the similarity of phenotypes between these patients and SRPS patients with mutations in the IFT43 gene (614068; see SRTD18, 617866), Duran et al. (2017) analyzed cultured chondrocytes from the SRTD7 patients and observed decreased IFT43 levels.
Short-Rib Thoracic Dysplasia 7/20 with Polydactyly
In a male infant (R04-176A) with SRTD and polydactyly, Toriyama et al. (2016) identified double heterozygosity for a W311L mutation in the WDR35 gene (613602.0013) and a truncating mutation in the INTU gene (Q276X; 610621.0003). The patient died in the neonatal period.
Caparros-Martin, J. A., De Luca, A., Cartault, F., Aglan, M., Temtamy, S., Otaify, G. A., Mehrez, M., Valencia, M., Vazquez, L., Alessandri, J.-L., Nevado, J., Rudda-Arenas, I., Heath, K. E., Digilio, M. C., Dallapiccola, B., Goodship, J. A., Mill, P., Lapunzina, P., Ruiz-Perez, V. L. Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Hum. Molec. Genet. 24: 4126-4137, 2015. [PubMed: 25908617] [Full Text: https://doi.org/10.1093/hmg/ddv152]
Duran, I., Taylor, S. P., Zhang, W., Martin, J., Qureshi, F., Jacques, S. M., Wallerstein, R., Lachman, R. S., Nickerson, D. A., Bamshad, M., Cohn, D. H., Krakow, D. Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia. Cilia 6: 7, 2017. Note: Electronic Article. [PubMed: 28400947] [Full Text: https://doi.org/10.1186/s13630-017-0051-y]
Huber, C., Cormier-Daire, V. Ciliary disorder of the skeleton. Am. J. Med. Genet. 160C: 165-174, 2012. [PubMed: 22791528] [Full Text: https://doi.org/10.1002/ajmg.c.31336]
Kannu, P., mcFarlane, J. H., Savarirayan, R., Aftimos, S. An unclassifiable short rib-polydactyly syndrome with acromesomelic hypomineralization and campomelia in siblings. Am. J. Med. Genet. 143A: 2607-2611, 2007. [PubMed: 17935248] [Full Text: https://doi.org/10.1002/ajmg.a.31989]
Mill, P., Lockhart, P. J., Fitzpatrick, E., Mountford, H. S., Hall, E. A., Reijns, M. A. M., Keighren, M., Bahlo, M., Bromhead, C. J., Budd, P., Aftimos, S., Delatycki, M. B., Savarirayan, R., Jackson, I. J., Amor, D. J. Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am. J. Hum. Genet. 88: 508-515, 2011. [PubMed: 21473986] [Full Text: https://doi.org/10.1016/j.ajhg.2011.03.015]
Schmidts, M., Vodopiutz, J., Christou-Savina, S., Cortes, C. R., McInerney-Leo, A. M., Emes, R. D., Arts, H. H., Tuysuz, B., D'Silva, J., Leo, P. J., Giles, T. C., Oud, M. M., and 23 others. Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. Am. J. Hum. Genet. 93: 932-944, 2013. [PubMed: 24183451] [Full Text: https://doi.org/10.1016/j.ajhg.2013.10.003]
Toriyama, M., Lee, C., Taylor, S. P., Duran, I., Cohn, D. H., Bruel, A.-L., Tabler, J. M., Drew, K., Kelly, M. R., Kim, S., Park, T. J., Braun, D. A., and 21 others. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nature Genet. 48: 648-656, 2016. Note: Erratum: Nature Genet. 48: 970 only, 2016. [PubMed: 27158779] [Full Text: https://doi.org/10.1038/ng.3558]