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Title: Genetics and pathophysiology of coronal craniosynostosis revealed by next-generation DNA sequencing
Author: Sharma, Vikram Pramod
ISNI:       0000 0004 5920 5254
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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This thesis further delineates the molecular genetic basis of a relatively common craniofacial condition, coronal craniosynostosis. It used whole-exome sequencing to identify novel disease genes in patients with non-syndromic coronal synostosis and negative genetic testing. Initially, 2 patients were identified with damaging, frameshift mutations in a gene not previously linked with craniosynostosis – Transcription Factor 12 (TCF12). A further intronic mutation was identified in a third patient. This gene encodes a transcription factor that dimerises with TWIST1, mutations of which cause Saethre-Chotzen syndrome, also associated with coronal synostosis. Screening 344 undiagnosed patients identified 35 further mutations, all with coronal synostosis with 14 cases arising de novo. This work was published and testing for TCF12-related craniosynostosis was translated clinically. Significant non-penetrance (60%) was identified in mutation-positive relatives and the genetic background was investigated. Firstly, analysis of parental origins of de novo mutations identified 6 of paternal origin and helped refine haplotype assignment. Secondly, haplotype analysis of TCF12-mutation carriers revealed modest correlation with phenotypic status, but this was insufficient to be useful in clinical testing. Thirdly, TCF12 haplotypes were analysed for association with non-syndromic coronal synostosis, but no significant association was found. Further exome sequencing revealed a de novo frameshift mutation in Transcription Factor 20 (TCF20) in a patient with coronal synostosis and autism, although the mutation only correlated with the latter phenotype. Analysis of 5 trios revealed a novel variant in myosin heavy chain 4 (MYH4) in 1 family, although its role in suture development is uncertain. Reviewing pooled exome data from 19 mutation-negative patients revealed no further disease genes. In summary, this thesis describes novel gene discovery, defines a new clinical entity and investigates genetic background of penetrant and non-penetrant individuals. Further exome sequencing identified another disease gene, a de novo mutation and compiled lists of damaging variants to allow future work.
Supervisor: Wilkie, Andrew O. M. Sponsor: Children's Craniofacial Charity/John Radcliffe Hospital ; Weatherall Institute of Molecular Medicine ; NIHR Biomedical Research Centre ; University of Oxford ; Royal College of Surgeons of England
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Molecular genetics ; High-Throughput Screening ; Plastic and reconstructive surgery ; Genetics (medical sciences) ; Biology (medical sciences) ; Clinical genetics ; Medical Sciences ; Genetics (life sciences) ; craniosynostosis ; coronal synostosis ; exome sequencing ; high-throughput DNA sequencing ; TCF12-related craniosynostosis ; Saethre-Chotzen syndrome ; genetics ; craniofacial biology ; diagnostic outcomes