Gene ca
Inhoud
H1 Chromosomale basis van erfelijkheid ................................................................................................ 4
1) Inleiding en historiek .................................................................................................................. 4
2) Celcyclus ..................................................................................................................................... 4
2.1 Inleiding ..................................................................................................................................... 4
2.2 Proces ........................................................................................................................................ 4
2.3 Chromosomen ........................................................................................................................... 4
2.4 Celcyclus checkpoints ................................................................................................................ 4
3) Karyotypering ............................................................................................................................. 4
3.1 Opstelling ................................................................................................................................... 5
3.2 Het chromosoom ....................................................................................................................... 5
3.3 Mitose vs meiose ....................................................................................................................... 5
4) Gametogenese ........................................................................................................................... 6
4.1 Spermatogenese ........................................................................................................................ 6
4.2 Oögenese ................................................................................................................................... 6
H2 Klinische cytogenomica ...................................................................................................................... 7
1) Problemen in meiose.................................................................................................................. 7
2) Numerieke chromosomale defecten .......................................................................................... 7
3) Prenatale gene sche diagnos ek............................................................................................... 8
4) Structurele chromosomale afwijkingen ..................................................................................... 8
4.1 Ongebalanceerd ........................................................................................................................ 8
4.2 Gebalanceerd ............................................................................................................................ 8
4.3 Transloca es .............................................................................................................................. 8
4.4 Subtelomerische dele es – microdele e .................................................................................. 9
4.5 Recurrente microdele esyndromen .................................................................................... 10
5) Array CGH ................................................................................................................................. 11
5.1 Werking ................................................................................................................................... 11
5.2 Voor en nadelen ...................................................................................................................... 11
5.3 CHARGE syndroom .................................................................................................................. 11
5.4 Kleefstra syndroom .................................................................................................................. 11
5.5 1p36 dele esyndroom............................................................................................................. 12
1
, 5.6 Casus ........................................................................................................................................ 12
H3 Moleculaire basis v monogenische aandoeningen .......................................................................... 12
1) Inleiding – humaan genoom en gene sche varia e ................................................................ 12
1.1 Humaan genoom project ..................................................................................................... 12
1.2 Func es van het genoom ..................................................................................................... 13
1.3 Structuur genoom ................................................................................................................ 13
1.4 GnomAD ............................................................................................................................... 13
2) Basisbegrippen ......................................................................................................................... 13
3) Gene sche varianten – categorieën......................................................................................... 14
3.1 Basepaarsubs tu e ................................................................................................................. 14
3.2 Dele es en inser es ................................................................................................................ 15
3.3 Dynamische muta es .............................................................................................................. 15
4) Moleculaire effecten v varianten.............................................................................................. 15
4.1 Loss of func on ....................................................................................................................... 15
4.2 Gain of func on ....................................................................................................................... 16
5) Klinische effecten v varianten................................................................................................... 16
5.1 Hemoglobinopathiën ............................................................................................................... 16
5.2 Gene sche defecten in enzymen ............................................................................................ 17
5.3 Gene sche defecten in structuureiwi en ............................................................................... 18
5.4 Gene sche defecten in membranaire eiwi en ....................................................................... 18
H4 Overervingsvormen monogenische aandoeningen ......................................................................... 19
1) Algemene inleiding ................................................................................................................... 19
1.1 Principes van Mendel ........................................................................................................... 19
2) Mendeliaanse overerving ......................................................................................................... 19
2.1 OMIM....................................................................................................................................... 19
2.2 Autosomaal dominant en recessief ......................................................................................... 20
3) Complicerende factoren ........................................................................................................... 20
3.1 De novo muta es .................................................................................................................... 20
3.2 Gereduceerde penetran e ...................................................................................................... 20
3.3 lee ijdsgebonden penetran e ................................................................................................ 21
3.4 Variabele expressie .................................................................................................................. 21
3.5 Pleiotropie ............................................................................................................................ 21
3.6 Locus heterogeniteit ............................................................................................................ 22
4) Niet-Mendeliaanse overerving ................................................................................................. 22
4.1 Geslachtsgebonden ................................................................................................................. 22
4.2 X-inac va e ............................................................................................................................. 22
2
, 4.3 X-gebonden recessieve overerving .......................................................................................... 23
4.4 X-gebonden dominante overerving ......................................................................................... 24
4.5 Fragiele X syndroom ......................................................................................................... 24
4.6 Y-gebonden overerving ........................................................................................................ 25
4.7 Mitochondriale overerving .................................................................................................. 25
4.8 Germinaal mosaïcisme ......................................................................................................... 26
4.9 Genomische imprin ng ........................................................................................................ 26
4.10 An cipa e ........................................................................................................................ 27
H5 Erfelijke kankersyndromen ............................................................................................................... 28
1) Oorzaken van kanker ................................................................................................................ 28
2) Kanker: sporadisch, familiaal, erfelijk ....................................................................................... 28
3) Kanker: gene sche basis .......................................................................................................... 28
3.1 Knudson’s 2 hit hypothese....................................................................................................... 28
4) Loss of heterozygosity .............................................................................................................. 28
5) Tumor suppressor genen .......................................................................................................... 29
5.1 Caretakers ................................................................................................................................ 29
5.2 Gatekeepers............................................................................................................................. 29
6) Oncogenen ............................................................................................................................... 29
7) Erfelijke kankersyndromen ....................................................................................................... 29
7.1 Erfelijke colonkanker................................................................................................................ 29
7.2 Erfelijke borstkanker ................................................................................................................ 31
7.3 Neurofibromatose type I = NF1 ............................................................................................... 31
7.4 Algemene conclusies ............................................................................................................... 32
H6 Gene sche raadpleging in de prak jk.............................................................................................. 32
1) Popula egene ca ..................................................................................................................... 32
1.1 Allel- en genotypefrequen e ............................................................................................... 32
1.2 Wet van Hardy-Weinberg ..................................................................................................... 32
1.3 Dragerschapsfrequen e ....................................................................................................... 32
1.4 Consanguiniteit .................................................................................................................... 32
2) Klinische toepassingen gene sche raadpleging en tes ng ...................................................... 33
2.1 Herhalingsrisico’s o.b.v. theorema v Bayes .............................................................................. 33
2.2 Indica es voor gene sche counseling, tes ng en screening .................................................. 34
2.3 Ethische, legale en maatschappelijke aspecten ...................................................................... 37
3
, H1 Chromosomale basis van erfelijkheid
1) Inleiding en historiek
Begin 20e E:
o Chromosomen zijn dragers van erfelijk materiaal
o 1956: mens hee 46 chromosomen
1882: Flemming = grondlegger cytogene ca
o Cytogene ca = studie van chromosomen
2) Celcyclus
2.1 Inleiding
Welke cellen gebruiken voor onderzoek naar mitose?
o Stamcellen: want delen constant
o Sneldelende cellen: bv huid en darmen
o Beenmerg
Celcyclus duurt ongeveer 16-24 uur, mitose zelf 1 uur
2.2 Proces
Cel zit in G0 fase en w ges muleerd door platelet derived growth factor (PDGF) om naar G1
te gaan (bloedplaatjes geven signaal aan huid)
G1 fase: cel groeit als voorbereiding (8u)
S fase: DNA replica e (6u)
G2 fase: cel bereidt zich voor op deling (4.5u)
Mitose: deling (1u)
o Profase
o Prometafase
o Metafase
o Anafase
o Telofase
o Cytokinese
2.3 Chromosomen
Beva en veel eiwi en
Chroma den w door condensine en cohesine bij elkaar gehouden tot anafase
Pas dan mogen zusterchroma den van elkaar loskomen
2.4 Celcyclus checkpoints
= CDKs = cyclin dependent kinases
Controleren of groei gestart mag worden, er genoeg factoren aanwezig zijn, replica e juist is
Bv controleren op PDGF
Fouten hierin kunnen kanker veroorzaken
3) Karyotypering
= Chromosomenonderzoek
4
Inhoud
H1 Chromosomale basis van erfelijkheid ................................................................................................ 4
1) Inleiding en historiek .................................................................................................................. 4
2) Celcyclus ..................................................................................................................................... 4
2.1 Inleiding ..................................................................................................................................... 4
2.2 Proces ........................................................................................................................................ 4
2.3 Chromosomen ........................................................................................................................... 4
2.4 Celcyclus checkpoints ................................................................................................................ 4
3) Karyotypering ............................................................................................................................. 4
3.1 Opstelling ................................................................................................................................... 5
3.2 Het chromosoom ....................................................................................................................... 5
3.3 Mitose vs meiose ....................................................................................................................... 5
4) Gametogenese ........................................................................................................................... 6
4.1 Spermatogenese ........................................................................................................................ 6
4.2 Oögenese ................................................................................................................................... 6
H2 Klinische cytogenomica ...................................................................................................................... 7
1) Problemen in meiose.................................................................................................................. 7
2) Numerieke chromosomale defecten .......................................................................................... 7
3) Prenatale gene sche diagnos ek............................................................................................... 8
4) Structurele chromosomale afwijkingen ..................................................................................... 8
4.1 Ongebalanceerd ........................................................................................................................ 8
4.2 Gebalanceerd ............................................................................................................................ 8
4.3 Transloca es .............................................................................................................................. 8
4.4 Subtelomerische dele es – microdele e .................................................................................. 9
4.5 Recurrente microdele esyndromen .................................................................................... 10
5) Array CGH ................................................................................................................................. 11
5.1 Werking ................................................................................................................................... 11
5.2 Voor en nadelen ...................................................................................................................... 11
5.3 CHARGE syndroom .................................................................................................................. 11
5.4 Kleefstra syndroom .................................................................................................................. 11
5.5 1p36 dele esyndroom............................................................................................................. 12
1
, 5.6 Casus ........................................................................................................................................ 12
H3 Moleculaire basis v monogenische aandoeningen .......................................................................... 12
1) Inleiding – humaan genoom en gene sche varia e ................................................................ 12
1.1 Humaan genoom project ..................................................................................................... 12
1.2 Func es van het genoom ..................................................................................................... 13
1.3 Structuur genoom ................................................................................................................ 13
1.4 GnomAD ............................................................................................................................... 13
2) Basisbegrippen ......................................................................................................................... 13
3) Gene sche varianten – categorieën......................................................................................... 14
3.1 Basepaarsubs tu e ................................................................................................................. 14
3.2 Dele es en inser es ................................................................................................................ 15
3.3 Dynamische muta es .............................................................................................................. 15
4) Moleculaire effecten v varianten.............................................................................................. 15
4.1 Loss of func on ....................................................................................................................... 15
4.2 Gain of func on ....................................................................................................................... 16
5) Klinische effecten v varianten................................................................................................... 16
5.1 Hemoglobinopathiën ............................................................................................................... 16
5.2 Gene sche defecten in enzymen ............................................................................................ 17
5.3 Gene sche defecten in structuureiwi en ............................................................................... 18
5.4 Gene sche defecten in membranaire eiwi en ....................................................................... 18
H4 Overervingsvormen monogenische aandoeningen ......................................................................... 19
1) Algemene inleiding ................................................................................................................... 19
1.1 Principes van Mendel ........................................................................................................... 19
2) Mendeliaanse overerving ......................................................................................................... 19
2.1 OMIM....................................................................................................................................... 19
2.2 Autosomaal dominant en recessief ......................................................................................... 20
3) Complicerende factoren ........................................................................................................... 20
3.1 De novo muta es .................................................................................................................... 20
3.2 Gereduceerde penetran e ...................................................................................................... 20
3.3 lee ijdsgebonden penetran e ................................................................................................ 21
3.4 Variabele expressie .................................................................................................................. 21
3.5 Pleiotropie ............................................................................................................................ 21
3.6 Locus heterogeniteit ............................................................................................................ 22
4) Niet-Mendeliaanse overerving ................................................................................................. 22
4.1 Geslachtsgebonden ................................................................................................................. 22
4.2 X-inac va e ............................................................................................................................. 22
2
, 4.3 X-gebonden recessieve overerving .......................................................................................... 23
4.4 X-gebonden dominante overerving ......................................................................................... 24
4.5 Fragiele X syndroom ......................................................................................................... 24
4.6 Y-gebonden overerving ........................................................................................................ 25
4.7 Mitochondriale overerving .................................................................................................. 25
4.8 Germinaal mosaïcisme ......................................................................................................... 26
4.9 Genomische imprin ng ........................................................................................................ 26
4.10 An cipa e ........................................................................................................................ 27
H5 Erfelijke kankersyndromen ............................................................................................................... 28
1) Oorzaken van kanker ................................................................................................................ 28
2) Kanker: sporadisch, familiaal, erfelijk ....................................................................................... 28
3) Kanker: gene sche basis .......................................................................................................... 28
3.1 Knudson’s 2 hit hypothese....................................................................................................... 28
4) Loss of heterozygosity .............................................................................................................. 28
5) Tumor suppressor genen .......................................................................................................... 29
5.1 Caretakers ................................................................................................................................ 29
5.2 Gatekeepers............................................................................................................................. 29
6) Oncogenen ............................................................................................................................... 29
7) Erfelijke kankersyndromen ....................................................................................................... 29
7.1 Erfelijke colonkanker................................................................................................................ 29
7.2 Erfelijke borstkanker ................................................................................................................ 31
7.3 Neurofibromatose type I = NF1 ............................................................................................... 31
7.4 Algemene conclusies ............................................................................................................... 32
H6 Gene sche raadpleging in de prak jk.............................................................................................. 32
1) Popula egene ca ..................................................................................................................... 32
1.1 Allel- en genotypefrequen e ............................................................................................... 32
1.2 Wet van Hardy-Weinberg ..................................................................................................... 32
1.3 Dragerschapsfrequen e ....................................................................................................... 32
1.4 Consanguiniteit .................................................................................................................... 32
2) Klinische toepassingen gene sche raadpleging en tes ng ...................................................... 33
2.1 Herhalingsrisico’s o.b.v. theorema v Bayes .............................................................................. 33
2.2 Indica es voor gene sche counseling, tes ng en screening .................................................. 34
2.3 Ethische, legale en maatschappelijke aspecten ...................................................................... 37
3
, H1 Chromosomale basis van erfelijkheid
1) Inleiding en historiek
Begin 20e E:
o Chromosomen zijn dragers van erfelijk materiaal
o 1956: mens hee 46 chromosomen
1882: Flemming = grondlegger cytogene ca
o Cytogene ca = studie van chromosomen
2) Celcyclus
2.1 Inleiding
Welke cellen gebruiken voor onderzoek naar mitose?
o Stamcellen: want delen constant
o Sneldelende cellen: bv huid en darmen
o Beenmerg
Celcyclus duurt ongeveer 16-24 uur, mitose zelf 1 uur
2.2 Proces
Cel zit in G0 fase en w ges muleerd door platelet derived growth factor (PDGF) om naar G1
te gaan (bloedplaatjes geven signaal aan huid)
G1 fase: cel groeit als voorbereiding (8u)
S fase: DNA replica e (6u)
G2 fase: cel bereidt zich voor op deling (4.5u)
Mitose: deling (1u)
o Profase
o Prometafase
o Metafase
o Anafase
o Telofase
o Cytokinese
2.3 Chromosomen
Beva en veel eiwi en
Chroma den w door condensine en cohesine bij elkaar gehouden tot anafase
Pas dan mogen zusterchroma den van elkaar loskomen
2.4 Celcyclus checkpoints
= CDKs = cyclin dependent kinases
Controleren of groei gestart mag worden, er genoeg factoren aanwezig zijn, replica e juist is
Bv controleren op PDGF
Fouten hierin kunnen kanker veroorzaken
3) Karyotypering
= Chromosomenonderzoek
4
