Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome

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We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy.

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Figure 1: Schematic representation of POLR1D and POLR1C and facial phenotypes of individuals with mutations within POLR1D and POLR1C .


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We express our sincere gratitude to the cases, their parents and other family members for their participation in this study, as well as to the clinicians for sending blood samples. We want to thank the Laboratory for Diagnostic Genome Analysis (LDGA) in Leiden and the Forensisch Laboratorium voor DNA Onderzoek (FLDO), as well as the TCS team in Essen and Regensburg for their excellent technical assistance and Ivo Fokkema for his help with constructing the Leiden Open Variation Databases (LOVD). This work was part of the CRANIRARENetwork funded through a grant from the German Ministry of Research and Education to D.R.L. and D.W. (BMBF 01GM0802). The financial support of the National Institutes of Health Research Manchester Biomedical Research Centre and the Healing Foundation to J.D. and M.J.D. is gratefully acknowledged.

Author information

Mutation analysis: J.G.D., S.S., D.R.L.

Patient ascertainment including clinical data and/or TCOF1 mutation analysis: J.D., A.v.H., L.H.H., D.J.M.P., A.C.-d.B., C.D.-H., R.M., C.Z., B.K., A.M.C., J.F.T., A.J.M.H., U.H., M.J.D., D.W.

Array analysis: C.A.L.R.

Manuscript writing: J.G.D., M.J.D., D.R.L., M.H.B., D.W.

Study design: J.G.D., A.v.H., D.W.

All authors contributed to the final version of the paper.

Correspondence to Johannes G Dauwerse.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Tables 1 and 2 and Supplementary Figures 1–4 (PDF 3805 kb)

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