Genetica
Inhoud
1. Leerdoelen ....................................................................................................................................... 5
2. Algemeen......................................................................................................................................... 5
3. Zeldzame aandoening-erfelijke aandoening: situering ................................................................... 6
4. Oorzaken van erfelijke aandoeningen............................................................................................. 6
5. Wanneer denken een erfelijke aandoening? .................................................................................. 7
5.1 Dysmorfe kenmerken .............................................................................................................. 7
5.2 Neurocognitieve stoornis ........................................................................................................ 7
5.3 Clustering van symptomen ...................................................................................................... 7
5.4 Verdachte familiale anamnese ................................................................................................ 7
6. Weefsel voor genoomdiagnostiek................................................................................................... 8
7. Detectietechnieken voor DNA veranderingen ............................................................................... 8
7.1 Karyotypering .......................................................................................................................... 8
7.2 Fluorescent In Situ Hybridization (FISH) ................................................................................ 12
7.3 Array-CGH = micro-array ....................................................................................................... 13
7.4 CNV seq ................................................................................................................................. 14
7.5 Southern Blot......................................................................................................................... 14
7.6 Methylatie-specifieke PCR..................................................................................................... 15
7.7 NIPT ....................................................................................................................................... 16
7.8 Triplet-repeat PCR ................................................................................................................. 16
7.8.1 Fragile X syndroom ........................................................................................................ 16
7.9 Sanger sequencing................................................................................................................. 18
7.9.1 Achondroplasie (dwerggroei) ........................................................................................ 19
7.10 Next generation sequencing (NGS) ....................................................................................... 20
7.10.1 Targeted resequencing van gen panels ......................................................................... 21
A. Gehoorverlies .................................................................................................................... 21
B. Thoracaal AO aneurysma .................................................................................................. 21
C. Intellectual Deficit (ID)/Developmental Disorder (DD) ..................................................... 21
7.10.2 Whole exome sequencing ............................................................................................. 22
7.10.3 Whole genome sequencing ........................................................................................... 22
7.11 Casussen ................................................................................................................................ 22
7.11.1 Casus 1 ........................................................................................................................... 22
7.11.2 Casus 2 ........................................................................................................................... 23
1
,8. Genetische counseling en genetische aandoeningen ................................................................... 24
8.1 Genetische counseling........................................................................................................... 24
8.2 Ziekte van Huntington (HD) ................................................................................................... 25
8.2.1 Triade van symptomen HD ................................................................................................ 26
8.2.2 Oorzaak HD ........................................................................................................................ 26
8.2.3 Genetische counseling HD ................................................................................................. 27
8.3 Alzheimer dementie (Ad) ...................................................................................................... 27
8.3.1 Soorten Ad ......................................................................................................................... 27
8.3.2 Genetisch landschap.......................................................................................................... 28
A. Ad: mendeliaanse overerving ............................................................................................ 28
B. Ad: APOE............................................................................................................................ 28
8.4 Frontotemporele dementie (FTD) en Amyotrofe Lateraal Sclerose (ALS) ............................ 29
8.4.1 Genetische achtergrond FTD en ALS ............................................................................. 29
8.4.2 Genetische testing bij FTD en ALS ................................................................................. 29
8.5 Cerebral small vessel diseases............................................................................................... 30
8.5.1 CADASIL ......................................................................................................................... 30
8.5.2 Ziekte van Fabry ............................................................................................................ 31
8.5.3 COL4A1 en COL4A2-gerelateerde aandoening.............................................................. 31
9. Oncogenetica................................................................................................................................. 32
9.1 Sporadisch vs familiaal vs hereditaire kankers ...................................................................... 33
9.1.1 Wanneer denken aan erfelijke vorm v kanker .............................................................. 33
9.1.2 Overerving erfelijke kankersyndromen ......................................................................... 33
9.2 Erfelijke kankersyndromen.................................................................................................... 34
9.2.1 Colorectaal carcinoom (CRC) ......................................................................................... 34
A. Indicaties aanwezigheid erfelijk CRC ................................................................................. 34
B. HNPCC of Lynch ................................................................................................................. 34
C. Familiale adenomateuze polyposis (FAP) .......................................................................... 35
D. Attenuated FAP (aFAP) ...................................................................................................... 36
9.2.2 Erfelijke borstkanker en eierstokkanker (HBOC) ........................................................... 36
A. Criteria voor screening ...................................................................................................... 37
B. Hoge penetratie genen...................................................................................................... 37
C. Matige penetratie genen ................................................................................................... 37
9.2.3 Neurofibromatose type 1 (NF1) .................................................................................... 38
9.2.4 Von Hippel Lindau syndroom ........................................................................................ 38
9.2.5 Li-Fraumeni syndroom................................................................................................... 38
9.2.6 Birt-Hogg-Dubé syndroom............................................................................................. 39
2
, 9.3 Waarom genoomdiagnostiek ................................................................................................ 39
9.4 Besluit .................................................................................................................................... 40
10. Genetische aandoeningen ......................................................................................................... 40
10.1 Cardiogenetica....................................................................................................................... 40
10.1.1 Congenitale hartafwijkingen ......................................................................................... 40
10.1.2 Cardiomyopathieën ....................................................................................................... 40
A. Hypertrofische cardiomyopathieën .................................................................................. 40
B. Metabole Cardiomyopathieën .......................................................................................... 41
C. Gedilateerde cardiomyopathieën ..................................................................................... 41
D. Restrictieve cardiomyopathieën ....................................................................................... 41
E. Arythmogene cardiomyopathieën .................................................................................... 41
F. Mitochondriale cardiomyopathieën.................................................................................. 41
10.1.3 Chanellopathieën .......................................................................................................... 41
A. Long QT syndroom ............................................................................................................ 42
B. Brugada syndroom ............................................................................................................ 42
C. Catecholaminerge Polymorfe Ventrikel Tachycardie (CPVT) ............................................ 42
10.1.4 Genetische testing (voorgaande aandoeningen) .......................................................... 42
10.1.5 Thoracaal Aorta Aneurysma .......................................................................................... 43
10.2 Erfelijke Bindweefdelaandoeningen ..................................................................................... 43
10.2.1 Marfan syndroom, Loeys-Dietz en aanverwante syndromale FTAA (Familiale
Thoracale Aorta Aneurysma syndromen) ..................................................................................... 44
A. Marfan syndroom .............................................................................................................. 44
B. Loeys-Dietz Syndroom (LDS).............................................................................................. 45
10.2.2 Ehlers-Danlos syndromen.............................................................................................. 45
10.2.3 Osteogenesis imperfecta ............................................................................................... 46
10.2.4 Stickler syndroom .......................................................................................................... 46
10.3 Nefrogenetica ........................................................................................................................ 46
10.3.1 Chronische nierinsufficiëntie ......................................................................................... 46
10.3.2 Congenitale nierafwijkingen .......................................................................................... 47
10.3.3 Polycystische nierziekte................................................................................................. 47
A. Autosomaal dominant PKD (ADPKD) ................................................................................. 48
B. Autosomaal recessief PKD (ARPKD)................................................................................... 50
10.3.4 Alport Syndroom: collageen IV nefropathie .................................................................. 50
A. Genetica Alport ................................................................................................................. 50
B. Symptomen Alport ............................................................................................................ 51
10.4 Erfelijke thrombofilie............................................................................................................. 51
3
, 10.4.1 Genetica trombofilie ..................................................................................................... 52
10.4.2 Suggestieve teken vr erfelijke vormen v trombofilie .................................................... 52
10.4.3 Testen vr erfelijke trombofilie: wie, wanneer en waarom? .......................................... 52
10.5 Dyslipidemieën ...................................................................................................................... 53
10.5.1 Familiale hypercholesterolemie .................................................................................... 53
A. Genetica FH genen: LOF en GOF ....................................................................................... 53
B. Diagnose FH ....................................................................................................................... 53
C. Behandeling FH.................................................................................................................. 53
10.5.2 Familiale hypertriglyceridemieën .................................................................................. 54
A. Familiaal chylomicronemie syndroom .............................................................................. 54
B. Secundaire hypertriglyceridemie ...................................................................................... 54
10.6 Diabetes: MODY .................................................................................................................... 55
10.6.1 Diabetes mellitus type 1 ................................................................................................ 55
10.6.2 Diabetes mellitus type 2 ................................................................................................ 55
10.6.3 Maturity-onset diabetes of the young (MODY)............................................................. 55
11. Gentherapie............................................................................................................................... 56
11.1 Duchenne Muscular Dystrophy (DMD) ................................................................................. 56
11.1.1 Genetische ahtergrond Duchenne ................................................................................ 57
11.1.2 Therapeutische mogelijkheden DMD ............................................................................ 57
A. Read-through therapie: Ataluren (TranslarnaTM) ............................................................ 57
B. AON-gemedieerde exon skipping therapie ....................................................................... 58
C. Vector-gemedieerde gentherapie ..................................................................................... 59
D. Genome editing ................................................................................................................. 59
11.2 Spinale Musculaire Dystrofie (SMA) ...................................................................................... 59
11.3 Retinale dystrophieën ........................................................................................................... 59
11.3.1 Leber Congenital Amaurosis (LCA) ................................................................................ 60
A. RPE65-LCA (LCA2) .............................................................................................................. 60
B. CEP290-LCA (LCA10) .......................................................................................................... 60
11.4 CRISPR/cas9: genome editing................................................................................................ 61
11.4.1 Werking CRISPER/Cas .................................................................................................... 61
11.4.2 Barrières CRISPR/Cas9 ................................................................................................... 61
11.5 Genetische dienstverlening in België .................................................................................... 62
4
Inhoud
1. Leerdoelen ....................................................................................................................................... 5
2. Algemeen......................................................................................................................................... 5
3. Zeldzame aandoening-erfelijke aandoening: situering ................................................................... 6
4. Oorzaken van erfelijke aandoeningen............................................................................................. 6
5. Wanneer denken een erfelijke aandoening? .................................................................................. 7
5.1 Dysmorfe kenmerken .............................................................................................................. 7
5.2 Neurocognitieve stoornis ........................................................................................................ 7
5.3 Clustering van symptomen ...................................................................................................... 7
5.4 Verdachte familiale anamnese ................................................................................................ 7
6. Weefsel voor genoomdiagnostiek................................................................................................... 8
7. Detectietechnieken voor DNA veranderingen ............................................................................... 8
7.1 Karyotypering .......................................................................................................................... 8
7.2 Fluorescent In Situ Hybridization (FISH) ................................................................................ 12
7.3 Array-CGH = micro-array ....................................................................................................... 13
7.4 CNV seq ................................................................................................................................. 14
7.5 Southern Blot......................................................................................................................... 14
7.6 Methylatie-specifieke PCR..................................................................................................... 15
7.7 NIPT ....................................................................................................................................... 16
7.8 Triplet-repeat PCR ................................................................................................................. 16
7.8.1 Fragile X syndroom ........................................................................................................ 16
7.9 Sanger sequencing................................................................................................................. 18
7.9.1 Achondroplasie (dwerggroei) ........................................................................................ 19
7.10 Next generation sequencing (NGS) ....................................................................................... 20
7.10.1 Targeted resequencing van gen panels ......................................................................... 21
A. Gehoorverlies .................................................................................................................... 21
B. Thoracaal AO aneurysma .................................................................................................. 21
C. Intellectual Deficit (ID)/Developmental Disorder (DD) ..................................................... 21
7.10.2 Whole exome sequencing ............................................................................................. 22
7.10.3 Whole genome sequencing ........................................................................................... 22
7.11 Casussen ................................................................................................................................ 22
7.11.1 Casus 1 ........................................................................................................................... 22
7.11.2 Casus 2 ........................................................................................................................... 23
1
,8. Genetische counseling en genetische aandoeningen ................................................................... 24
8.1 Genetische counseling........................................................................................................... 24
8.2 Ziekte van Huntington (HD) ................................................................................................... 25
8.2.1 Triade van symptomen HD ................................................................................................ 26
8.2.2 Oorzaak HD ........................................................................................................................ 26
8.2.3 Genetische counseling HD ................................................................................................. 27
8.3 Alzheimer dementie (Ad) ...................................................................................................... 27
8.3.1 Soorten Ad ......................................................................................................................... 27
8.3.2 Genetisch landschap.......................................................................................................... 28
A. Ad: mendeliaanse overerving ............................................................................................ 28
B. Ad: APOE............................................................................................................................ 28
8.4 Frontotemporele dementie (FTD) en Amyotrofe Lateraal Sclerose (ALS) ............................ 29
8.4.1 Genetische achtergrond FTD en ALS ............................................................................. 29
8.4.2 Genetische testing bij FTD en ALS ................................................................................. 29
8.5 Cerebral small vessel diseases............................................................................................... 30
8.5.1 CADASIL ......................................................................................................................... 30
8.5.2 Ziekte van Fabry ............................................................................................................ 31
8.5.3 COL4A1 en COL4A2-gerelateerde aandoening.............................................................. 31
9. Oncogenetica................................................................................................................................. 32
9.1 Sporadisch vs familiaal vs hereditaire kankers ...................................................................... 33
9.1.1 Wanneer denken aan erfelijke vorm v kanker .............................................................. 33
9.1.2 Overerving erfelijke kankersyndromen ......................................................................... 33
9.2 Erfelijke kankersyndromen.................................................................................................... 34
9.2.1 Colorectaal carcinoom (CRC) ......................................................................................... 34
A. Indicaties aanwezigheid erfelijk CRC ................................................................................. 34
B. HNPCC of Lynch ................................................................................................................. 34
C. Familiale adenomateuze polyposis (FAP) .......................................................................... 35
D. Attenuated FAP (aFAP) ...................................................................................................... 36
9.2.2 Erfelijke borstkanker en eierstokkanker (HBOC) ........................................................... 36
A. Criteria voor screening ...................................................................................................... 37
B. Hoge penetratie genen...................................................................................................... 37
C. Matige penetratie genen ................................................................................................... 37
9.2.3 Neurofibromatose type 1 (NF1) .................................................................................... 38
9.2.4 Von Hippel Lindau syndroom ........................................................................................ 38
9.2.5 Li-Fraumeni syndroom................................................................................................... 38
9.2.6 Birt-Hogg-Dubé syndroom............................................................................................. 39
2
, 9.3 Waarom genoomdiagnostiek ................................................................................................ 39
9.4 Besluit .................................................................................................................................... 40
10. Genetische aandoeningen ......................................................................................................... 40
10.1 Cardiogenetica....................................................................................................................... 40
10.1.1 Congenitale hartafwijkingen ......................................................................................... 40
10.1.2 Cardiomyopathieën ....................................................................................................... 40
A. Hypertrofische cardiomyopathieën .................................................................................. 40
B. Metabole Cardiomyopathieën .......................................................................................... 41
C. Gedilateerde cardiomyopathieën ..................................................................................... 41
D. Restrictieve cardiomyopathieën ....................................................................................... 41
E. Arythmogene cardiomyopathieën .................................................................................... 41
F. Mitochondriale cardiomyopathieën.................................................................................. 41
10.1.3 Chanellopathieën .......................................................................................................... 41
A. Long QT syndroom ............................................................................................................ 42
B. Brugada syndroom ............................................................................................................ 42
C. Catecholaminerge Polymorfe Ventrikel Tachycardie (CPVT) ............................................ 42
10.1.4 Genetische testing (voorgaande aandoeningen) .......................................................... 42
10.1.5 Thoracaal Aorta Aneurysma .......................................................................................... 43
10.2 Erfelijke Bindweefdelaandoeningen ..................................................................................... 43
10.2.1 Marfan syndroom, Loeys-Dietz en aanverwante syndromale FTAA (Familiale
Thoracale Aorta Aneurysma syndromen) ..................................................................................... 44
A. Marfan syndroom .............................................................................................................. 44
B. Loeys-Dietz Syndroom (LDS).............................................................................................. 45
10.2.2 Ehlers-Danlos syndromen.............................................................................................. 45
10.2.3 Osteogenesis imperfecta ............................................................................................... 46
10.2.4 Stickler syndroom .......................................................................................................... 46
10.3 Nefrogenetica ........................................................................................................................ 46
10.3.1 Chronische nierinsufficiëntie ......................................................................................... 46
10.3.2 Congenitale nierafwijkingen .......................................................................................... 47
10.3.3 Polycystische nierziekte................................................................................................. 47
A. Autosomaal dominant PKD (ADPKD) ................................................................................. 48
B. Autosomaal recessief PKD (ARPKD)................................................................................... 50
10.3.4 Alport Syndroom: collageen IV nefropathie .................................................................. 50
A. Genetica Alport ................................................................................................................. 50
B. Symptomen Alport ............................................................................................................ 51
10.4 Erfelijke thrombofilie............................................................................................................. 51
3
, 10.4.1 Genetica trombofilie ..................................................................................................... 52
10.4.2 Suggestieve teken vr erfelijke vormen v trombofilie .................................................... 52
10.4.3 Testen vr erfelijke trombofilie: wie, wanneer en waarom? .......................................... 52
10.5 Dyslipidemieën ...................................................................................................................... 53
10.5.1 Familiale hypercholesterolemie .................................................................................... 53
A. Genetica FH genen: LOF en GOF ....................................................................................... 53
B. Diagnose FH ....................................................................................................................... 53
C. Behandeling FH.................................................................................................................. 53
10.5.2 Familiale hypertriglyceridemieën .................................................................................. 54
A. Familiaal chylomicronemie syndroom .............................................................................. 54
B. Secundaire hypertriglyceridemie ...................................................................................... 54
10.6 Diabetes: MODY .................................................................................................................... 55
10.6.1 Diabetes mellitus type 1 ................................................................................................ 55
10.6.2 Diabetes mellitus type 2 ................................................................................................ 55
10.6.3 Maturity-onset diabetes of the young (MODY)............................................................. 55
11. Gentherapie............................................................................................................................... 56
11.1 Duchenne Muscular Dystrophy (DMD) ................................................................................. 56
11.1.1 Genetische ahtergrond Duchenne ................................................................................ 57
11.1.2 Therapeutische mogelijkheden DMD ............................................................................ 57
A. Read-through therapie: Ataluren (TranslarnaTM) ............................................................ 57
B. AON-gemedieerde exon skipping therapie ....................................................................... 58
C. Vector-gemedieerde gentherapie ..................................................................................... 59
D. Genome editing ................................................................................................................. 59
11.2 Spinale Musculaire Dystrofie (SMA) ...................................................................................... 59
11.3 Retinale dystrophieën ........................................................................................................... 59
11.3.1 Leber Congenital Amaurosis (LCA) ................................................................................ 60
A. RPE65-LCA (LCA2) .............................................................................................................. 60
B. CEP290-LCA (LCA10) .......................................................................................................... 60
11.4 CRISPR/cas9: genome editing................................................................................................ 61
11.4.1 Werking CRISPER/Cas .................................................................................................... 61
11.4.2 Barrières CRISPR/Cas9 ................................................................................................... 61
11.5 Genetische dienstverlening in België .................................................................................... 62
4
