title: Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies.
abstract: Short-rib thoracic dystrophies (SRTDs) are congenital disorders due to defects in primary cilium function. SRTDs are recessively inherited with mutations identified in 14 genes to date (comprising 398 exons). Conventional mutation detection (usually by iterative Sanger sequencing) is inefficient and expensive, and often not undertaken. Whole exome massive parallel sequencing has been used to identify new genes for SRTD (WDR34, WDR60 and IFT172); however, the clinical utility of whole exome sequencing (WES) has not been established. WES was performed in 11 individuals with SRTDs. Compound heterozygous or homozygous mutations were identified in six confirmed SRTD genes in 10 individuals (IFT172, DYNC2H1, TTC21B, WDR60, WDR34 and NEK1), giving overall sensitivity of 90.9%. WES data from 993 unaffected individuals sequenced using similar technology showed two individuals with rare (minor allele frequency <0.005) compound heterozygous variants of unknown significance in SRTD genes (specificity >99%). Costs for consumables, laboratory processing and bioinformatic analysis were <AU$850 per sample. WES is sensitive, specific, efficient and cost-effective for mutation screening as well as gene discovery in SRTDs and can be considered a first-line methodology for mutation identification in affected individuals.
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: McInerney-Leo
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Harris
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Leo
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
authors.forename: M S
authors.initials: MS
authors.lastname: Marshall
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Gardiner
authors.affiliation: West of Scotland Genetics Service, Southern General Hospital, Glasgow, G51 4TF, UK.
authors.forename: E
authors.initials: E
authors.lastname: Kinning
authors.affiliation: Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.
authors.forename: H Y
authors.initials: HY
authors.lastname: Leong
authors.affiliation: Genetic Services of Western Australia, Subiaco, WA 6008, Australia.|School of Paediatrics and Child Health, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: F
authors.initials: F
authors.lastname: McKenzie
authors.affiliation: Genetics Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.
authors.forename: W P
authors.initials: WP
authors.lastname: Ong
authors.affiliation: Department of Pediatrics and Adolescent Medicine Medical University of Vienna, A-1090 Vienna Waehringerguertel 18-20, Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Vodopiutz
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Wicking
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Discipline of Genetic Medicine, The University of Sydney, Sydney, Australia.|Academic Department of Medical Genetics, Sydney Children's Hospital Network (Westmead), Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Zankl
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.|Department of Endocrinology, James Mayne Building, Royal Brisbane and Women's Hospital, Butterfield Road, Herston, QLD 4029, Australia.|The University of Queensland, University of Queensland Centre for Clinical Research, Herston, QLD 4029, Australia.
authors.forename: E L
authors.initials: EL
authors.lastname: Duncan
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D056445:Cytoplasmic Dyneins / Q000235:genetics; D003598:Cytoskeletal Proteins; D059472:Exome / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015203:Reproducibility of Results; D012272:Ribs / Q000002:abnormalities*; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods*; D013909:Thorax / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056445:Cytoplasmic Dyneins; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases; C099883:DYNC2H1 protein, human; C000599964:IFT172 protein, human; C000594121:TTC21B protein, human; C543203:WDR34 protein, human; C584144:DYNC2I1 protein, human; C000606914:NEK1 protein, human
keywords: Jeune syndrome; ciliopathy; exome sequencing; primary cilia; short-rib polydactyly