ORPHA: 1515;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.12 | Short-rib thoracic dysplasia 16 with or without polydactyly | 617102 | Autosomal recessive | 3 | IFT52 | 617094 |
A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-16 with or without polydactyly (SRTD16) is caused by homozygous or compound heterozygous mutation in the IFT52 gene (617094) on chromosome 20q13.
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 with or without polydactyly, see SRTD1 (208500).
Girisha et al. (2016) described a 3-year-old girl from a consanguineous Indian family who was born with bilateral postaxial polydactyly of the hands and mild respiratory distress. She had significant motor delay and progressive deterioration of peripheral vision. MRI of the brain at age 6 months showed a hypoplastic corpus callosum. Examination at age 3 years revealed dolichocephaly, tall forehead, low-set ears, telecanthus, midface hypoplasia, broad and depressed nasal bridge, full cheeks, thick and everted vermilion of upper and lower lips, and widely spaced, small carious teeth. Her thorax was short and narrow, with a protuberant abdomen. She had short limbs with marked brachydactyly and laxity in both hands and feet. Radiography showed short metacarpals, short metatarsals, short phalanges, cone-shaped epiphyses of phalanges, hypoplastic distal phalanges, and striking angel-shaped middle phalanges. Ophthalmologic examination revealed hypermetropia and salt-and-pepper appearance of the fundus, suggesting degenerative retinal changes.
Zhang et al. (2016) reported a nonconsanguineous family in which features consistent with short-rib polydactyly syndrome were identified prenatally in 2 fetuses. Radiographic findings at 20 and 23 weeks' gestation, respectively, showed undermineralized skulls, narrow thoraces with moderately shortened ribs and sharp angulations of some lower thoracic ribs, flat appearance to acetabular roofs, reverse campomelia of humeri, mildly bent femurs, and no polydactyly. Histologic examination of the cartilage growth plate from the second fetus showed a very short and disorganized hypertrophic zone suggesting impairment of the transition from proliferating to hypertrophic chondrocytes, with an irregular margin at the transition between cartilage and bone.
Chen et al. (2018) reported an 11-year-old girl who had nystagmus and severe visual impairment from birth, as well as mild skeletal dysplasia. Evaluation at age 5 years showed visual acuity of 20/200 bilaterally, with attenuated retinal vessel on funduscopy. At age 11, her best corrected vision was hand motion for both eyes, and funduscopy revealed pigment deposits and waxy optic discs as well as attenuated retinal vasculature bilaterally. Optical coherence tomography demonstrated loss of the ellipsoid layer in the macula bilaterally, and both scotopic and photopic responses were diminished on electroretinography. The authors concluded that this severe retinal dystrophy from birth represented Leber congenital amaurosis (LCA; see 204000). The proband also exhibited mild mental retardation and severe growth retardation, with narrow chest, short ribs, and micromelic limbs. In addition, she had dental dysplasia, with several missing teeth.
Dupont et al. (2019) studied a family in which 2 fetuses, 1 male and 1 female, showed signs of SRTD and had mutations in the IFT52 gene. Both fetuses had short ribs, narrow chest, short long bones, and postaxial polydactyly of both hands and 1 foot. The male fetus also exhibited tortuous ureters and left pelviectasis.
The transmission pattern of SRTD16 in the family reported by Girisha et al. (2016) was consistent with autosomal recessive inheritance.
In a 3-year-old Indian girl with short stature, a short narrow thorax and postaxial polydactyly, Girisha et al. (2016) performed exome sequencing and identified homozygosity for a nonsense mutation in the IFT52 gene (R142X; 617094.0001), for which her unaffected consanguineous parents were heterozygous.
By exome sequencing of DNA from 1 of 2 fetuses from a nonconsanguineous family with features of short-rib polydactyly syndrome, Zhang et al. (2016) identified compound heterozygosity for a 1-bp deletion (617094.0002) and a missense mutation (A199T; 617094.0003) in the IFT52 gene. The unaffected parents were each heterozygous for one of the mutations; neither mutation was found in public variant databases.
In an 11-year-old girl with features of both skeletal and retinal ciliopathy, who exhibited mild SRTD as well as Leber congenital amaurosis, Chen et al. (2018) identified homozygosity for a missense mutation in the IFT52 gene (T186A; 617094.0004) that segregated fully with disease in the family and was not found in public variant databases. Functional analysis showed reduced ciliary length with the T186A mutant that was consistent with a loss-of-function mechanism.
In 140 individuals from 116 families with SRTD, Dupont et al. (2019) performed exome sequencing that targeted cilia-related genes. In 2 fetuses from 1 family (F1), they identified compound heterozygosity for mutations in the IFT52 gene: a maternally inherited missense mutation (N98S; 617094.0005) and a paternally inherited insertion/deletion (617094.0006).
Chen, X., Wang, X., Jiang, C., Xu, M., Liu, Y., Qi, R., Qi, X., Sun, X., Xie, P., Liu, Q., Yan, B., Sheng, X., Zhao, C. IFT52 as a novel candidate for ciliopathies involving retinal degeneration. Invest. Ophthal. Vis. Sci. 59: 4581-4589, 2018. [PubMed: 30242358] [Full Text: https://doi.org/10.1167/iovs.17-23351]
Dupont, M. A., Humbert, C., Huber, C., Siour, Q., Guerrera, I. C., Jung, V., Christensen, A., Pouliet, A., Garfa-Traore, M., Nitschke, P., Injeyan, M., Millar, K., and 11 others. Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. Hum. Molec. Genet. 28: 2720-2737, 2019. [PubMed: 31042281] [Full Text: https://doi.org/10.1093/hmg/ddz091]
Girisha, K. M., Shukla, A., Trujillano, D., Bhavani, G. S., Hebbar, M., Kadavigere, R., Rolfs, A. A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet. 90: 536-539, 2016. [PubMed: 26880018] [Full Text: https://doi.org/10.1111/cge.12762]
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]
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]
Zhang, W., Taylor, S. P., Nevarez, L., Lachman, R. S., Nickerson, D. A., Bamshad, M., University of Washington Center for Mendelian Genomics Consortium, Krakow, D., Cohn, D. H. IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome. Hum. Molec. Genet. 25: 4012-4020, 2016. [PubMed: 27466190] [Full Text: https://doi.org/10.1093/hmg/ddw241]