title: Identification of Intragenic Exon Deletions and Duplication of TCF12 by Whole Genome or Targeted Sequencing as a Cause of TCF12-Related Craniosynostosis.
abstract: TCF12-related craniosynostosis can be caused by small heterozygous loss-of-function mutations in TCF12. Large intragenic rearrangements, however, have not been described yet. Here, we present the identification of four large rearrangements in TCF12 causing TCF12-related craniosynostosis. Whole-genome sequencing was applied on the DNA of 18 index cases with coronal synostosis and their family members (43 samples in total). The data were analyzed using an autosomal-dominant disease model. Structural variant analysis reported intragenic exon deletions (of sizes 84.9, 8.6, and 5.4 kb) in TCF12 in three different families. The results were confirmed by deletion-specific PCR and dideoxy-sequence analysis. Separately, targeted sequencing of the TCF12 genomic region in a patient with coronal synostosis identified a tandem duplication of 11.3 kb. The pathogenic effect of this duplication was confirmed by cDNA analysis. These findings indicate the importance of screening for larger rearrangements in patients suspected to have TCF12-related craniosynostosis.
authors.affiliation: Erasmus MC, Department of Plastic and Reconstructive Surgery and Hand Surgery, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jacqueline A C
authors.initials: JA
authors.lastname: Goos
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Fenwick
authors.affiliation: Erasmus MC, Department of Bioinformatics, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Sigrid M A
authors.initials: SM
authors.lastname: Swagemakers
authors.affiliation: Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.affiliation: NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Samantha J L
authors.initials: SJ
authors.lastname: Knight
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Stephen R F
authors.initials: SR
authors.lastname: Twigg
authors.affiliation: Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: A Jeannette M
authors.initials: AJ
authors.lastname: Hoogeboom
authors.affiliation: Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Marieke F
authors.initials: MF
authors.lastname: van Dooren
authors.affiliation: Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Magielsen
authors.affiliation: Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Wall
authors.affiliation: Erasmus MC, Department of Plastic and Reconstructive Surgery and Hand Surgery, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Irene M J
authors.initials: IM
authors.lastname: Mathijssen
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK.
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
authors.affiliation: Erasmus MC, Department of Bioinformatics, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.affiliation: Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D003398:Craniosynostoses / Q000235:genetics*; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*; D017384:Sequence Deletion; D020080:Tandem Repeat Sequences
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C073366:TCF12 protein, human
keywords: TCF12-related craniosynostosis; exon duplication; intragenic exon deletion; rearrangements