ORPHA: 861; DO: 0080790;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q12.2 | Treacher Collins syndrome 2 | 613717 | Autosomal dominant; Autosomal recessive | 3 | POLR1D | 613715 |
A number sign (#) is used with this entry because of evidence that Treacher Collins syndrome-2 (TCS2) is caused by heterozygous mutation in the POLR1D gene (613715) on chromosome 13q12. One POLR1D mutation has been reported that, in homozygosity only, results in TCS2.
Treacher Collins syndrome is a disorder of craniofacial development characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss (Dauwerse et al., 2011).
For additional phenotypic information and a discussion of genetic heterogeneity of Treacher Collins syndrome, see TCS1 (154500).
Vincent et al. (2016) reported the clinical features of the 7 patients they identified with POLR1D mutations causing TCS2. Six of the 7 had downward slanting palpebral fissures and/or malar hypoplasia, 5 had conductive deafness, and all 7 had mandibular hypoplasia. Between 40% and 60% of this small group had atresia of the external ear canal, coloboma of the lower eyelid, facial asymmetry, or projection of scalp hair on the lateral cheek. One in 6 patients examined had cleft palate, and 1 in 6 had a spinal malformation. None had any of the rare features reported in TCS1. Whether this was an effect of sample size or was due to the molecular basis was unknown.
Treacher Collins syndrome-2 is an autosomal dominant disorder (Dauwerse et al., 2011).
Schaefer et al. (2014) reported 2 unrelated consanguineous Turkish families in which Treacher Collins syndrome-2 was inherited in an autosomal recessive pattern.
In a 3-year-old boy with Treacher Collins syndrome who was negative for mutation in the TCOF1 gene (606847), Dauwerse et al. (2011) performed genomewide copy number analysis and identified a 156-kb de novo deletion at chromosome 13q12.2 that encompassed the entire POLR1D gene (613715) and exon 1 of the LNX2 gene (609733). Sequence analysis of POLR1D and LNX2 in 10 additional Treacher Collins patients who were negative for mutations in TCOF1 revealed a boy who was heterozygous for a nonsense mutation in POLR1D (R87X; 613715.0001). Analysis of POLR1D in a further 242 individuals with typical TCS or with clinical findings in the TCS phenotypic spectrum who were negative for TCOF1 mutations yielded 10 heterozygous nonsense mutations and 7 heterozygous missense mutations in 20 index cases (see, e.g., 613715.0002-613715.0006).
Schaefer et al. (2014) reported 4 affected children from 2 unrelated consanguineous families with mild Treacher Collins syndrome (TCS2; 613717) who shared the same homozygous missense mutation in the POLR1D gene (L55V; 613715.0007). Both sets of unaffected parents and the unaffected sister of the first proband were heterozygous for the mutation. functional analysis of TCOF1 by real-time quantitative RT-PCR demonstrated a 50% reduction in transcripts, compatible with the hypothesis that this mutation impairs RNA polymerase and results in a lower amount of mature dimeric ribosomes.
Dauwerse, J. G., Dixon, J., Seland, S., Ruivenkamp, C. A. L., van Haeringen, A., Hoefsloot, L. H., Peters, D. J. M., Clement-de Boers, A., Daumer-Haas, C., Maiwald, R., Zweier, C., Kerr, B., Cobo, A. M., Toral, J. F., Hoogeboom, A. J. M., Lohmann, D. R., Hehr, U., Dixon, M. J., Breuning, M. H., Wieczorek, D. Mutations in gene encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nature Genet. 43: 20-22, 2011. [PubMed: 21131976] [Full Text: https://doi.org/10.1038/ng.724]
Schaefer, E., Collet, C., Genevieve, D., Vincent, M., Lohmann, D. R., Sanchez, E., Bolender, C., Eliot, M.-M., Nurnberg, G., Passos-Bueno, M.-R., Wieczorek, D., Van Maldergem, L., Doray, B. Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome. Genet. Med. 16: 720-724, 2014. [PubMed: 24603435] [Full Text: https://doi.org/10.1038/gim.2014.12]
Vincent, M., Genevieve, D., Ostertag, A., Marlin, S., Lacombe, D., Martin-Coignard, D., Coubes, C., David, A., Lyonnet, S., Vilain, C., Dieux-Coeslier, A., Manouvrier, S., and 44 others. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet. Med. 18: 49-56, 2016. Note: Erratum: Genet. Med. 17: 686 only, 2015. [PubMed: 25790162] [Full Text: https://doi.org/10.1038/gim.2015.29]