ORPHA: 861; DO: 0080792;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
2q14.1 | Treacher-Collins syndrome 4 | 618939 | Autosomal dominant | 3 | POLR1B | 602000 |
A number sign (#) is used with this entry because of evidence that Treacher Collins syndrome-4 (TCS4) is caused by heterozygous mutation in the POLR1B gene (602000) on chromosome 2q14.
Treacher Collins syndrome-4 (TCS4) is characterized by craniofacial dysmorphisms including downslanting palpebral fissures, malar and mandibular hypoplasia, and microtia. Most patients have conductive deafness with atretic external ear canals. Choanal atresia and cleft palate have also been observed (Sanchez et al., 2020).
Sanchez et al. (2020) reported 6 patients from 5 families with Treacher Collins syndrome and mutations in the POLR1B gene. The patients all exhibited downslanting palpebral fissures and malar hypoplasia, and most also had mandibular hypoplasia as well as microtia, atresia of the external ear canal, and conductive deafness. Facial asymmetry was present in 3 patients, 3 had cleft palate, and 2 had choanal atresia. In the neonatal period, 5 of the 6 patients required nasogastric or gastrostomy tube feedings, and 3 underwent intubation or tracheostoma.
The transmission pattern of TCS4 in 2 families reported by Sanchez et al. (2020) was consistent with autosomal dominant inheritance; in 1 family the proband inherited the mutation from her mosaic father. The heterozygous mutations in 3 other patients occurred de novo.
By trio exome sequencing in 6 patients from a previously described TCS cohort (Vincent et al., 2016) who were negative for mutation in known mandibulofacial dysostosis-associated genes, Sanchez et al. (2020) identified 2 probands with heterozygous missense mutations in the POLR1B gene: a de novo R1003C substitution (602000.0001) in patient 1, and an S682R substitution (602000.0003) in patient 2 and her mother (patient 3). By international collaboration, including GeneMatcher in 1 case, the authors ascertained 3 more patients with TCS and mutations in the POLR1B gene, including 2 more patients (patients 4 and 6) with the R1003C variant. The remaining patient (patient 5) was heterozygous for an R1003S substitution (602000.0002) that was also found to be present in mosaicism in her mildly affected father.
Sanchez, E., Laplace-Builhe, B., Mau-Them, F. T., Richard, E., Goldenberg, A., Toler, T. L., Guignard, T., Gatinois, V., Vincent, M., Blanchet, C., Boland, A., Bihoreau, M. T., and 16 others. POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Genet. Med. 22: 547-556, 2020. [PubMed: 31649276] [Full Text: https://doi.org/10.1038/s41436-019-0669-9]
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]