دانلود کتاب Genetics and Genomics of Eye Disease: Advancing to Precision Medicine

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Cover GENETICS AND GENOMICS OF EYE DISEASE: Advancing to Precision Medicine Copyright Dedication Contributors Preface Acknowledgments Part I: Introduction to gene mapping 1 Timeline of key discoveries in ophthalmic genetics References 2 Segregation, linkage, GWAS, and sequencing Segregation analysis Segregation: How is a trait inherited? Simple vs. complex segregation analysis Advantages of segregation analysis Disadvantages of segregation analysis Segregation analyses for ocular traits and diseases Linkage analysis What is genetic linkage? Linkage: What genetic variation contributes to a trait? Types of linkage analysis Advantages of linkage analysis Disadvantages of linkage analysis Linkage analyses for ocular traits and diseases Genome-wide association studies What is a GWAS? Advantages and disadvantages of GWAS Examples of GWAS for eye diseases DNA sequencing Overview of sequencing technologies: Past to present Types of sequencing Advantages and disadvantages of sequencing References Part II: Genomics in the eye 3 Whole-exome sequencing and whole-genome sequencing Development of NGS technologies Illumina sequencing Targeted enrichment sequencing Targeted enrichment techniques Hybridization-based enrichment Molecular inversion probes Targeted amplicon sequencing Whole-exome sequencing Commercially available WES kits Panel vs WES Whole-genome sequencing technologies WES vs WGS Long-read technologies SMRT sequencing by PacBio Nanopore sequencing by ONT Linked-reads sequencing by 10x Genomics WES/WGS data analysis Future direction/perspectives References 4 RNA sequencing and transcriptome analysis History of transcriptome analysis methods RNA-Seq Library preparation Data analysis-Alignment and count generation Data analysis-Novel feature detection Data analysis-Downstream applications RNA-Seq in the eye Transcriptome analyses Models of disease Disease genes and therapeutic targets Concluding remarks References 5 Noncoding genome in eye disease Introduction to the noncoding genome MicroRNAs and the eye lncRNAs and the eye Noncoding RNAs and eye disease Age-related macular degeneration Diabetic retinopathy Glaucoma Retinitis pigmentosa Retinoblastoma Other diseases of the eye Concluding remarks References Part III: Mendelian disorders and high penetrant mutations 6 Genetic architecture of inherited retinal disease Spectrum and evaluation of the clinical phenotype of IRD Inheritance pattern Mechanistic pathways culminating in photoreceptor degeneration Ciliary transport and intracellular trafficking Photoreceptor development Phototransduction cascade The visual cycle Synaptic transmission defects Spliceosome complex Interphotoreceptor matrix Genetic heterogeneity in IRD Genetic heterogeneity in monogenic IRDs Allelic heterogeneity in IRD Incomplete penetrance in RP11 Mutation spectrum of IRD Regulatory and noncoding variants Large DNA duplication and deletion in IRD Splice-site and alternative transcript variants Conclusion References 7 Early-onset glaucoma Clinical features of JOAG Epidemiology of JOAG Age of onset Myopia Intraocular pressure Response to therapy Optic disc morphology Inheritance pattern MYOC and JOAG MYOC-associated glaucoma clinical phenotype (JOAG) MYOC-associated glaucoma clinical phenotype (POAG) MYOC pathophysiology Case report (MYOC-associated JOAG) OPTN and juvenile-onset open-angle glaucoma OPTN-associated glaucoma clinical phenotype Function of OPTN Association between OPTN and ALS Effects of OPTN mutations Transgenic mouse models of OPTN-associated glaucoma Knock-in mouse model of OPTN-associated glaucoma Case report (OPTN-associated glaucoma) TBK1 and JOAG TBK1-associated glaucoma clinical phenotype Function of TBK1 Effects of TBK1 duplications Transgenic mouse model of TBK1-associated glaucoma Case report (TBK1-associated glaucoma) Genetic testing and JOAG Gene-directed therapies Targeted therapies for MYOC-associated glaucoma OPTN and TBK1-associated glaucoma direct therapies Acknowledgments References 8 Bardet-Biedl syndrome Bardet-Biedl syndrome Mode of inheritance Clinical diagnosis Pleotropic phenotypes Retinal degeneration in BBS Using animal models to study retinal degeneration in BBS In vitro molecular mechanisms of BBS Transcriptional variation Other disorders attributed to BBS genes Leber congenital amaurosis Joubert syndrome Senior-Løken syndrome Nonsyndromic retinal degeneration BBS research and advancing biotechnology Conclusions References 9 Hereditary predisposition to uveal melanoma Introduction Genetic versus environmental basis of UM Familial uveal melanoma UM clustering with other cancers Highly penetrance genes with reported germline mutations in UM BRCA1-associated protein 1 (BAP1) Breast cancer 2 (BRCA2) Mismatch repair genes (MLH1 and MSH6) MBD4 Birt-Hogg-Dube Syndrome and UM (FLCN) CDKN2A/ARF and CDK4 Low penetrant genes HERC2/OCA2 TERT/CLPTM1L Summary and conclusions References Part IV: Complex disorders and low effect-size risk factors 10 Age-related macular degeneration Introduction Genomic studies in AMD Genome-wide association studies Case-control studies for rare variants Family-based studies for rare variants Effect sizes of common versus rare variants Contribution of common versus rare variants Functional effect of common versus rare variants Effect of AMD-associated variants on disease mechanisms Effect of the common CFH p.Tyr402His variant Effect of common variants at the ARMS2/HTRA1 locus Effect of genetic variants on gene expression Effect of genetic variants on the complement system Effect of genetic variants on lipoprotein homeostasis Effect of variants on extracellular matrix remodeling Effect of variants on neovascularization Other omics studies in AMD Effect of genetic variants on treatment response Dietary supplementation Anti-VEGF treatment Complement inhibitors Conclusions Acknowledgments References 11 Genetics of primary open-angle glaucoma Introduction Primary open-angle glaucoma Symptoms and diagnosis Therapies POAG genetics Linkage analyses MYOC, ASB10, and EFEMP1 Interleukin 20 receptor subunit β Optineurin and TANK-binding kinase 1 WD repeat domain 36 Neurotrophin 4 Genome-wide association studies Caveolins 1 and 2 Transmembrane and coiled-coil domain 1 CDKN2B antisense RNA 1 SIX homeobox 6 ATP-binding cassette subfamily A member 1 GDP-mannose 4,6-dehydratase and forkhead box C1 Actin filament-associated protein 1 Thioredoxin reductase 2 Ataxin 2 Endophenotypes Intraocular pressure Central cornea thickness Vertical CDR RNFL thickness POAG pathways Conclusion References 12 Genetics of diabetic retinopathy Genetic linkage analysis Candidate gene studies Aldose reductase Endothelial nitric oxide synthase Receptor for advanced glycation end products Vascular endothelial growth factor rs2010963 rs833061 rs699947 rs3025039 Other VEGF polymorphisms Other candidate genes Insulin receptor Angiotensin-converting enzyme Growth factor receptor-bound protein 2 C-reactive protein P-selectin High-mobility-group A1 Solute carrier family 19 member 2/3 Genome-wide association studies Whole-exome sequencing Epigenetics DNA methylation Histone modifications MicroRNAs Mitochondrial DNA Summary Acknowledgments References 13 Genetics of keratoconus Introduction Human cornea anatomy Keratoconus Clinical signs and diagnosis Treatment modalities Genetics of KC Genome-wide linkage studies in KC Genome-wide association studies in KC KC candidate genes identified by Sanger sequencing or targeted genotyping Conclusion Conflict of Interest References Part V: Genetic testing and genetic risk prediction 14 Genetic testing of various eye disorders Overview of genetic techniques Detecting coding variation Variants leading to aberrant splicing captured by targeted panels Deep-intronic variants Variants leading to altered gene expression Detecting structural variants (CNV and chromosomal aberration) Genetic modifiers of phenotypic severity of IRDs Ocular phenotype-A marker of syndromic disease Conclusions References 15 Genetic risk scores in complex eye disorders Introduction Risk scores and their applications Ocular traits with well-established risk loci and risk scores Age-related macular degeneration Genetics of AMD Risk scores in AMD Glaucoma Genetics of glaucoma Risk scores in glaucoma Myopia and refractive error Genetics of myopia and refractive error Risk scores in myopia and refractive error Other complex ocular traits Age-related cataract and diabetic retinopathy Fuchs endothelial corneal dystrophy (FECD) Looking forward: capabilities and limitations of risk scores Polygenic risk scores Clinical utility of risk scores References Part VI: Gene-based therapy 16 Gene therapy for inherited retinal diseases Introduction History Vectors Current studies Nonsyndromic RP RPGR RLBP1 PDE6ß MERTK Syndromic RP Usher syndrome Bardet-Biedl syndrome Stargardt disease X-linked retinoschisis Achromatopsia Choroideremia Leber congenital amaurosis Limitations of gene therapy Future perspectives References 17 Gene therapy in animal models Introduction Inherited retinal degenerations Classification Type of dystrophy Clinical nomenclature Basic biology of common IRDs Animal models of inherited retinal degenerations Vertebrate models of IRD Gene therapies of IRDs Challenges References Part VII: Big data and precision medicine 18 Pleiotropy in eye disease and related traits Introduction Numerous genes show pleiotropic effects GWAS SNPs show pleiotropic effects Genetic risk scores show pleiotropic effects Implications for genomic medicine Other aspects of pleiotropy Conclusions Acknowledgments References Web Resources 19 Advancing to precision medicine through big data and artificial intelligence Introduction Precision medicine Advancing precision medicine with big data Spearheading precision medicine with AI Ancient wisdom on medicine Conclusion References Index Back Cover