title: Next generation diagnostics of heritable connective tissue disorders.
abstract: Finding pathogenic mutations in monogenic diseases represents one of the significant milestones of late 20th century molecular genetics. Mutation data can improve genetic counseling, assist disease modeling and provide a basis for translational research and therapeutics. The logistics of detecting disease mutations, however, has not always been easy or straightforward. Traditional approaches using genetic linkage or candidate gene analysis have often been laborious and expensive, but the advent of next generation sequencing technologies is changing the very nature of modern-day gene discovery and mutation detection. The application of whole-exome and whole-genome sequencing has demonstrated how these new approaches can improve diagnostic sensitivity as well as disclose completely novel and unsuspected disease-gene associations. Use of next generation sequencing in inherited diseases that display genetic heterogeneity is already a cost-effective methodology for mutation detection. Further reductions in sequencing costs and machine run time, as well as improved bioinformatics, are likely to lead to the incorporation of next generation sequencing into routine diagnostics within clinical genetics. In the short term, the impact of next generation sequencing on the genetically diverse and clinically protean heritable connective tissue disorders is likely to mean more comprehensive documentation of individual mutations. Longer term, dissection of bioinformatics data may lead to further insight into individual prognosis and an era of new personal therapeutics.
authors.affiliation: St John's Institute of Dermatology, King's College London, Floor 9 Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Amr
authors.initials: A
authors.lastname: Salam
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, Floor 8 Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, Floor 8 Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Kristina L
authors.initials: KL
authors.lastname: Stone
authors.affiliation: St John's Institute of Dermatology, King's College London, Floor 9 Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Takeichi
authors.affiliation: As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait.
authors.forename: Arti
authors.initials: A
authors.lastname: Nanda
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: St John's Institute of Dermatology, King's College London, Floor 9 Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK. Electronic address: john.mcgrath@kcl.ac.uk.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D001483:Base Sequence; D003240:Connective Tissue Diseases / Q000175:diagnosis* / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D025202:Molecular Diagnostic Techniques; D009154:Mutation
keywords: Collagen; Extracellular matrix; Mutation; Whole-exome sequencing