SAMENVATTING HUMANE
MOLECULAIRE GENETICA
2e Bachelor Biomedische Wetenschappen
,Inhoudsopgave
Het humaan genoom en genetische variatie ................................................................... 6
Inleiding ............................................................................................................... 6
Basisbegrippen ...................................................................................................... 8
Genetische varianten - categorieën ........................................................................... 9
Basepaarsubstitutie .......................................................................................... 9
Niet-coderend................................................................................................. 12
Moleculaire effecten van varianten .......................................................................... 17
Klinische effecten van varianten........................................................................... 19
Hemoglobinopathieën ..................................................................................... 19
Genetische defecten in enzymen ...................................................................... 21
Genetische defecten in structuureiwitten.......................................................... 21
Genetische defecten in membranaire eiwitten................................................... 24
Technieken voor genetische testing en genoomanalyse ............................................. 26
Materiaal ............................................................................................................ 26
PCR ................................................................................................................... 27
First generation sequencing ................................................................................. 28
Second generation sequencing ............................................................................ 28
Next generation sequencing (NGS) ................................................................... 28
Sequencing-by-synthesis (SBS) ........................................................................ 29
Single-molecule technologieën............................................................................ 30
Long-read sequencing ..................................................................................... 30
Optical Genome Mapping ................................................................................ 33
Medische genoomanalyse ................................................................................... 33
Gerichte sequencing van genen of genenpanels ................................................ 34
Whole exome sequencing (WES) ...................................................................... 34
Whole genome sequencing (WGS) .................................................................... 34
Genetisch bepaalde ziekten: chromosomale afwijkingen en structurele varianten ...... 35
Inleiding ............................................................................................................. 35
Cytogenetische/cytogenomische nomenclatuur en technologie ............................ 35
Chromosoomonderzoek .................................................................................. 35
Klinische cytogenetica en chromosomale afwijkingen ........................................... 36
, Numerieke afwijkingen .................................................................................... 36
Structurele afwijkingen .................................................................................... 37
FISH ............................................................................................................... 41
Genetisch bepaalde ziekten – monogenische aandoeningen ..................................... 43
Algemene inleiding.............................................................................................. 43
Mendeliaanse overerving ..................................................................................... 43
OMIM ............................................................................................................. 43
Autosomaal dominante overerving ................................................................... 43
Autosomaal recessieve overerving .................................................................... 44
Complicerende factoren .................................................................................. 45
Niet-Mendeliaanse overerving ............................................................................. 47
Geslachtsgebonden ........................................................................................ 47
Niet-traditionele overervingsvormen ................................................................. 48
Genetisch bepaalde aandoeningen: complexe (multifactoriële) aandoeningen ........... 56
Introductie: polygenische theorie van Fisher ......................................................... 56
Linkage disequilibrium (LD) ................................................................................. 57
Identificatie van genen voor complexe aandoeningen ............................................ 58
Casus: lengte .................................................................................................. 59
Knelpunten van associatiestudies ........................................................................ 60
Multiple testing ............................................................................................... 60
Missing heritability........................................................................................... 60
Hoe kunnen genetische varianten een effect uitoefenen? ...................................... 61
Gen-omgeving interacties .................................................................................... 61
Genetische basis van kanker ................................................................................... 62
Moleculaire basis van kanker ............................................................................... 62
Inleiding.......................................................................................................... 62
Klassieke chemo-therapie ................................................................................ 62
Precisie oncologie ........................................................................................... 63
Welke cellulaire processen zijn verstoord? ........................................................ 64
Evidentie dat kanker een genetische aandoening is ............................................ 65
Muismodellen ................................................................................................. 66
Oncogenen ..................................................................................................... 67
, Types .............................................................................................................. 67
Tumor-suppressorgenen .................................................................................. 69
Moleculaire therapie ........................................................................................ 70
Biomerkers ..................................................................................................... 71
Predictieve biomerkers voor precisie oncologie ................................................. 71
Familiale kankersyndromen ................................................................................. 72
Inleiding.......................................................................................................... 72
Tweelingstudies .............................................................................................. 73
Familiale en erfelijke vormen van kanker ........................................................... 73
Het Knudson 2-hit model en LOH...................................................................... 74
Voorbeelden van enkele frequente familiale kanker syndromen .......................... 76
Polygenische Risicoscore (PRS) ........................................................................ 83
Statistische genetica .............................................................................................. 84
Populatiegenetica ............................................................................................... 84
Allel- en genotypefrequentie............................................................................. 84
Wet van Hardy- Weinberg ................................................................................. 84
Consanguiniteit en inteelt ................................................................................ 84
Ricisoberekening monogenische aandoeningen.................................................... 86
Herhalingsrisico .............................................................................................. 86
Theorema van Bayes ........................................................................................ 86
Mappen van genen .............................................................................................. 88
Recombinatie ................................................................................................. 88
Linkage equilibrium en desiquilibrium ............................................................... 89
Linkage analyse ............................................................................................... 90
Segregatie-onderzoek van gekoppelde merkers ................................................. 91
Klinische toepassingen van humane genetica........................................................... 93
Diagnostisch onderzoek ...................................................................................... 93
Dragerschapsonderzoek...................................................................................... 93
Presymptomatische of predictieve of voorspellende testing ................................... 93
Prenatale diagnostiek .......................................................................................... 94
Algemeen ....................................................................................................... 94
NIPT ............................................................................................................... 94
MOLECULAIRE GENETICA
2e Bachelor Biomedische Wetenschappen
,Inhoudsopgave
Het humaan genoom en genetische variatie ................................................................... 6
Inleiding ............................................................................................................... 6
Basisbegrippen ...................................................................................................... 8
Genetische varianten - categorieën ........................................................................... 9
Basepaarsubstitutie .......................................................................................... 9
Niet-coderend................................................................................................. 12
Moleculaire effecten van varianten .......................................................................... 17
Klinische effecten van varianten........................................................................... 19
Hemoglobinopathieën ..................................................................................... 19
Genetische defecten in enzymen ...................................................................... 21
Genetische defecten in structuureiwitten.......................................................... 21
Genetische defecten in membranaire eiwitten................................................... 24
Technieken voor genetische testing en genoomanalyse ............................................. 26
Materiaal ............................................................................................................ 26
PCR ................................................................................................................... 27
First generation sequencing ................................................................................. 28
Second generation sequencing ............................................................................ 28
Next generation sequencing (NGS) ................................................................... 28
Sequencing-by-synthesis (SBS) ........................................................................ 29
Single-molecule technologieën............................................................................ 30
Long-read sequencing ..................................................................................... 30
Optical Genome Mapping ................................................................................ 33
Medische genoomanalyse ................................................................................... 33
Gerichte sequencing van genen of genenpanels ................................................ 34
Whole exome sequencing (WES) ...................................................................... 34
Whole genome sequencing (WGS) .................................................................... 34
Genetisch bepaalde ziekten: chromosomale afwijkingen en structurele varianten ...... 35
Inleiding ............................................................................................................. 35
Cytogenetische/cytogenomische nomenclatuur en technologie ............................ 35
Chromosoomonderzoek .................................................................................. 35
Klinische cytogenetica en chromosomale afwijkingen ........................................... 36
, Numerieke afwijkingen .................................................................................... 36
Structurele afwijkingen .................................................................................... 37
FISH ............................................................................................................... 41
Genetisch bepaalde ziekten – monogenische aandoeningen ..................................... 43
Algemene inleiding.............................................................................................. 43
Mendeliaanse overerving ..................................................................................... 43
OMIM ............................................................................................................. 43
Autosomaal dominante overerving ................................................................... 43
Autosomaal recessieve overerving .................................................................... 44
Complicerende factoren .................................................................................. 45
Niet-Mendeliaanse overerving ............................................................................. 47
Geslachtsgebonden ........................................................................................ 47
Niet-traditionele overervingsvormen ................................................................. 48
Genetisch bepaalde aandoeningen: complexe (multifactoriële) aandoeningen ........... 56
Introductie: polygenische theorie van Fisher ......................................................... 56
Linkage disequilibrium (LD) ................................................................................. 57
Identificatie van genen voor complexe aandoeningen ............................................ 58
Casus: lengte .................................................................................................. 59
Knelpunten van associatiestudies ........................................................................ 60
Multiple testing ............................................................................................... 60
Missing heritability........................................................................................... 60
Hoe kunnen genetische varianten een effect uitoefenen? ...................................... 61
Gen-omgeving interacties .................................................................................... 61
Genetische basis van kanker ................................................................................... 62
Moleculaire basis van kanker ............................................................................... 62
Inleiding.......................................................................................................... 62
Klassieke chemo-therapie ................................................................................ 62
Precisie oncologie ........................................................................................... 63
Welke cellulaire processen zijn verstoord? ........................................................ 64
Evidentie dat kanker een genetische aandoening is ............................................ 65
Muismodellen ................................................................................................. 66
Oncogenen ..................................................................................................... 67
, Types .............................................................................................................. 67
Tumor-suppressorgenen .................................................................................. 69
Moleculaire therapie ........................................................................................ 70
Biomerkers ..................................................................................................... 71
Predictieve biomerkers voor precisie oncologie ................................................. 71
Familiale kankersyndromen ................................................................................. 72
Inleiding.......................................................................................................... 72
Tweelingstudies .............................................................................................. 73
Familiale en erfelijke vormen van kanker ........................................................... 73
Het Knudson 2-hit model en LOH...................................................................... 74
Voorbeelden van enkele frequente familiale kanker syndromen .......................... 76
Polygenische Risicoscore (PRS) ........................................................................ 83
Statistische genetica .............................................................................................. 84
Populatiegenetica ............................................................................................... 84
Allel- en genotypefrequentie............................................................................. 84
Wet van Hardy- Weinberg ................................................................................. 84
Consanguiniteit en inteelt ................................................................................ 84
Ricisoberekening monogenische aandoeningen.................................................... 86
Herhalingsrisico .............................................................................................. 86
Theorema van Bayes ........................................................................................ 86
Mappen van genen .............................................................................................. 88
Recombinatie ................................................................................................. 88
Linkage equilibrium en desiquilibrium ............................................................... 89
Linkage analyse ............................................................................................... 90
Segregatie-onderzoek van gekoppelde merkers ................................................. 91
Klinische toepassingen van humane genetica........................................................... 93
Diagnostisch onderzoek ...................................................................................... 93
Dragerschapsonderzoek...................................................................................... 93
Presymptomatische of predictieve of voorspellende testing ................................... 93
Prenatale diagnostiek .......................................................................................... 94
Algemeen ....................................................................................................... 94
NIPT ............................................................................................................... 94
