title: Whole exome sequencing is an efficient, sensitive and specific method of mutation detection in osteogenesis imperfecta and Marfan syndrome.
abstract: Osteogenesis imperfecta (OI) and Marfan syndrome (MFS) are common Mendelian disorders. Both conditions are usually diagnosed clinically, as genetic testing is expensive due to the size and number of potentially causative genes and mutations. However, genetic testing may benefit patients, at-risk family members and individuals with borderline phenotypes, as well as improving genetic counseling and allowing critical differential diagnoses. We assessed whether whole exome sequencing (WES) is a sensitive method for mutation detection in OI and MFS. WES was performed on genomic DNA from 13 participants with OI and 10 participants with MFS who had known mutations, with exome capture followed by massive parallel sequencing of multiplexed samples. Single nucleotide polymorphisms (SNPs) and small indels were called using Genome Analysis Toolkit (GATK) and annotated with ANNOVAR. CREST, exomeCopy and exomeDepth were used for large deletion detection. Results were compared with the previous data. Specificity was calculated by screening WES data from a control population of 487 individuals for mutations in COL1A1, COL1A2 and FBN1. The target capture of five exome capture platforms was compared. All 13 mutations in the OI cohort and 9/10 in the MFS cohort were detected (sensitivity=95.6%) including non-synonymous SNPs, small indels (<10 bp), and a large UTR5/exon 1 deletion. One mutation was not detected by GATK due to strand bias. Specificity was 99.5%. Capture platforms and analysis programs differed considerably in their ability to detect mutations. Consumable costs for WES were low. WES is an efficient, sensitive, specific and cost-effective method for mutation detection in patients with OI and MFS. Careful selection of platform and analysis programs is necessary to maximize success.
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital , Brisbane, Queensland, Australia.
authors: Aideen M
authors: AM
authors: McInerney-Leo
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital , Brisbane, Queensland, Australia.
authors: Mhairi S
authors: MS
authors: Marshall
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital , Brisbane, Queensland, Australia.
authors: Brooke
authors: B
authors: Gardiner
authors: Medical Genetics, The University Hospital Ghent , Gent, Belgium.
authors: Paul J
authors: PJ
authors: Coucke
authors: University of Antwerp, Antwerp University Hospital , Antwerp, Belgium.
authors: Lut
authors: L
authors: Van Laer
authors: University of Antwerp, Antwerp University Hospital , Antwerp, Belgium ; Department of Genetics, Radboud University Medical Center , Nijmegen, The Netherlands.
authors: Bart L
authors: BL
authors: Loeys
authors: The Roslin Institute and R(D)SVS, University of Edinburgh , Midlothian, UK.
authors: Kim M
authors: KM
authors: Summers
authors: Medical Genetics, The University Hospital Ghent , Gent, Belgium.
authors: Sofie
authors: S
authors: Symoens
authors: The University of Qld Northside Clinical School, Prince Charles Hospital , Chermside, Queensland, Australia.
authors: Jennifer A
authors: JA
authors: West
authors: The University of Qld Northside Clinical School, Prince Charles Hospital , Chermside, Queensland, Australia.
authors: Malcolm J
authors: MJ
authors: West
authors: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre , Oxford, UK.
authors: B
authors: B
authors: Paul Wordsworth
authors: The University of Queensland, UQ Centre for Clinical Research , Herston, Queensland, Australia ; Sydney Medical School, University of Sydney , Sydney, New South Wales, Australia ; Academic Department of Medical Genetics, The Children's Hospital at Westmead , Sydney, New South Wales, Australia.
authors: Andreas
authors: A
authors: Zankl
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital , Brisbane, Queensland, Australia.
authors: Paul J
authors: PJ
authors: Leo
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital , Brisbane, Queensland, Australia.
authors: Matthew A
authors: MA
authors: Brown
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital , Brisbane, Queensland, Australia ; Department of Endocrinology, Royal Brisbane and Women's Hospital , Herston, Queensland, Australia.
authors: Emma L
authors: EL
authors: Duncan