Genetics
EERSTE MASTER FARMACIE 2018-2019
GERT MATTHIJS
,Inhoud
Ex-examenvragen................................................................................................................................. 4
1. Inleiding .......................................................................................................................................... 4
1.1. Soorten mutaties op chromosomaal niveau ..................................................................... 5
1.1.1. Nonsense mutations..................................................................................................... 5
1.1.2. Missense mutations ...................................................................................................... 5
1.1.3. Splicing mutations......................................................................................................... 5
1.1.4. Neutral variants ............................................................................................................. 5
1.1.5. Insertions/ deletions...................................................................................................... 5
2. Recessieve aandoeningen .......................................................................................................... 6
2.1. Overervingspatroon .............................................................................................................. 6
2.2. Implicaties .............................................................................................................................. 6
2.3. Hardy-Weinberg equilibrium................................................................................................ 6
2.4. Cystic fibrosis ........................................................................................................................ 7
2.4.1. Ivacaftor.......................................................................................................................... 8
2.5. CF (and other recessive diseases) – risks and rare molecular findings ...................... 8
2.6. Atypische presentaties ......................................................................................................... 9
3. Dominante aandoeningen ......................................................................................................... 10
3.1. Ziekte van Huntington ........................................................................................................ 10
3.2. Achondroplasie (dwerggroei) ............................................................................................ 10
3.3. Neurofibromatosis I ............................................................................................................ 12
3.4. Osteogenesis imperfecta tarda ......................................................................................... 12
3.5. Marfan syndroom ................................................................................................................ 13
3.6. Afwijkende overervingspatronen ...................................................................................... 14
3.7. Familial hypercholesterolemia (FH) ................................................................................. 14
3.7.1. General features ......................................................................................................... 14
3.7.2. Behandeling ................................................................................................................. 14
3.7.3. Inheritance patterns and genes ................................................................................ 14
4. X-gebonden aandoeningen ....................................................................................................... 17
4.1. X inactivation center → Xist .............................................................................................. 18
4.2. Hemofilie A........................................................................................................................... 19
4.3. Duchenne muscular dystrophy/ Becker muscular dystrophy ....................................... 19
4.4. Fragiele X syndroom .......................................................................................................... 20
4.4.1. Fragile-X and transmitting males – The Sherman Paradox ................................. 20
4.4.2. Genetisch defect ......................................................................................................... 21
4.4.3. Correlatie klinische en moleculaire gegevens ........................................................ 21
1
, 4.5. Incontinentia pigmenti ........................................................................................................ 22
4.6. Rett syndrome ..................................................................................................................... 22
4.7. Neonatal severe encephalopathy..................................................................................... 23
5. Moleculaire diagnostiek van familiale kankersyndromen ..................................................... 24
5.1. Borstkankergenen: BRCA1 en BRCA2 ........................................................................... 24
5.1.1. Mechanism................................................................................................................... 25
5.1.2. Indicaties voor een mutatieanalyse.......................................................................... 26
5.1.3. Preventieve strategie.................................................................................................. 27
5.1.4. Behandeling ................................................................................................................. 27
5.1.5. Andere borstkankergenen ......................................................................................... 29
5.2. Other cancer genes? .......................................................................................................... 29
6. Chromosomen ............................................................................................................................. 30
6.1. Inleiding ................................................................................................................................ 30
6.1.1. Benamingen................................................................................................................. 30
6.1.2. Chromosomal anomalies ........................................................................................... 31
6.1.3. Robertiaanse translocaties (EXAMEN) ................................................................... 35
6.2. FISH: Fluorescent In Situ Hybridisation ......................................................................... 38
6.3. Technieken voor prenataal onderzoek ............................................................................ 40
6.4. Algemene extra info ........................................................................................................... 43
7. Next Generation Sequencing (NGS) ....................................................................................... 44
7.1. Sanger sequencing............................................................................................................. 44
7.2. Genetische diagnostiek ..................................................................................................... 44
Algemene begrippen: (EXAMEN) ...................................................................................................... 45
7.3. Parallel sequencing ............................................................................................................ 45
8. Prenatal diagnosis and NIPD .................................................................................................... 53
8.1. Invasive procedures ........................................................................................................... 53
8.2. Non-invasive procedures ................................................................................................... 53
8.2.1. NIPT .............................................................................................................................. 55
8.2.2. Preimplantation genetic diagnosis (PGD) ............................................................... 55
9. Farmacogenetica ........................................................................................................................ 58
9.1. Algemene principes ............................................................................................................ 58
9.1.1. The right dose for the right patient. .......................................................................... 58
9.1.2. Find the right patient for the right therapy. .............................................................. 58
9.2. Metabolisatiesnelheid is genetisch bepaald ................................................................... 59
9.3. Voorbeelden ........................................................................................................................ 61
9.3.1. Abacavir (ziagen®) sensitivity ................................................................................... 61
2
, 9.3.2. Carbamazepine (Tegretol) ........................................................................................ 61
9.3.3. Azathioprine (Imuran) and Mercaptopurin (Puri-Nethol)....................................... 61
9.3.4. fluorouracil, capecitabine, tegafur ............................................................................ 62
9.4. Companion testing – precision medicine ........................................................................ 62
10. Multifactoriële aandoeningen ................................................................................................ 65
10.1. Examples ......................................................................................................................... 65
10.2. Inleiding ............................................................................................................................ 66
10.3. Discontinue variabelen ................................................................................................... 66
10.4. Multifactoriële aandoeningen ........................................................................................ 67
10.4.1. Alzheimer’s disease................................................................................................ 67
10.4.2. Type 2 diabetes....................................................................................................... 68
10.4.3. Herhalingskans ....................................................................................................... 68
10.4.4. Pylorushypertrofie ................................................................................................... 68
10.4.5. Heritabiliteit .............................................................................................................. 68
10.5. Genetische zelftests en autonomie .............................................................................. 69
3
,Ex-examenvragen
- EXAMEN
o 4 or 5 questions
o 5 multiple choice without guess correction
- PGD (preimplantation diagnostics)
o Wat is het?
o Bespreek voor- en nadelen.
- Een man met 46 XX karyotype, welk genetisch defect?
- Foto van kind met Down
o Welke aandoening?
o Welk gen defect en hoe ontstaat het?
- Pylorusstenose, meisje minder kans dan jongen dus als zus al pylorusstenose heeft,
toekomstige broer meer kans, waarom?
- 5 meerkeuze vragen zonder giscorrectie.
- Geef 2 voorbeelden van GM met hun indicaties en werkingsmechanisme gebruikt voor precision
medicine.
- Wat is exoom sequencing en wat is het voordeel in de moleculaire diagnostiek?
- Geef 3 of 4 specifieke eigenschappen van X-gebonden erfelijke aandoeningen.
- Beschrijf de factoren en situaties die incidentie en herhalingskans van multifactoriële
aandoeningen bepalen.
- Wat is de invloed van CYP2D6 op de activiteit van nortriptyline? Bespreek op niveau van DNA.
- Wat is NIPD en bespreek de voordelen ervan.
1. Inleiding
- Humane, medische, klinische, moleculaire genetica
- Constitutionele aandoeningen
- Verworven aandoeningen
- Monogene aandoeningen
- Chromosomale afwijkingen
- Multifactoriële aandoeningen
4
, 1.1. Soorten mutaties op chromosomaal niveau
1.1.1.Nonsense mutations
- No amino acids, just stopcodon
1.1.2.Missense mutations
- Amino acid is replaced
- Phylogenic inheritance: The evolution conserved the mutation
1.1.3.Splicing mutations
1.1.4.Neutral variants
- Change in codon doesn’t affect amino acids
1.1.5.Insertions/ deletions
- In frame mutations: triplet is OK
- Out of frame mutations: triplet not OK
5
EERSTE MASTER FARMACIE 2018-2019
GERT MATTHIJS
,Inhoud
Ex-examenvragen................................................................................................................................. 4
1. Inleiding .......................................................................................................................................... 4
1.1. Soorten mutaties op chromosomaal niveau ..................................................................... 5
1.1.1. Nonsense mutations..................................................................................................... 5
1.1.2. Missense mutations ...................................................................................................... 5
1.1.3. Splicing mutations......................................................................................................... 5
1.1.4. Neutral variants ............................................................................................................. 5
1.1.5. Insertions/ deletions...................................................................................................... 5
2. Recessieve aandoeningen .......................................................................................................... 6
2.1. Overervingspatroon .............................................................................................................. 6
2.2. Implicaties .............................................................................................................................. 6
2.3. Hardy-Weinberg equilibrium................................................................................................ 6
2.4. Cystic fibrosis ........................................................................................................................ 7
2.4.1. Ivacaftor.......................................................................................................................... 8
2.5. CF (and other recessive diseases) – risks and rare molecular findings ...................... 8
2.6. Atypische presentaties ......................................................................................................... 9
3. Dominante aandoeningen ......................................................................................................... 10
3.1. Ziekte van Huntington ........................................................................................................ 10
3.2. Achondroplasie (dwerggroei) ............................................................................................ 10
3.3. Neurofibromatosis I ............................................................................................................ 12
3.4. Osteogenesis imperfecta tarda ......................................................................................... 12
3.5. Marfan syndroom ................................................................................................................ 13
3.6. Afwijkende overervingspatronen ...................................................................................... 14
3.7. Familial hypercholesterolemia (FH) ................................................................................. 14
3.7.1. General features ......................................................................................................... 14
3.7.2. Behandeling ................................................................................................................. 14
3.7.3. Inheritance patterns and genes ................................................................................ 14
4. X-gebonden aandoeningen ....................................................................................................... 17
4.1. X inactivation center → Xist .............................................................................................. 18
4.2. Hemofilie A........................................................................................................................... 19
4.3. Duchenne muscular dystrophy/ Becker muscular dystrophy ....................................... 19
4.4. Fragiele X syndroom .......................................................................................................... 20
4.4.1. Fragile-X and transmitting males – The Sherman Paradox ................................. 20
4.4.2. Genetisch defect ......................................................................................................... 21
4.4.3. Correlatie klinische en moleculaire gegevens ........................................................ 21
1
, 4.5. Incontinentia pigmenti ........................................................................................................ 22
4.6. Rett syndrome ..................................................................................................................... 22
4.7. Neonatal severe encephalopathy..................................................................................... 23
5. Moleculaire diagnostiek van familiale kankersyndromen ..................................................... 24
5.1. Borstkankergenen: BRCA1 en BRCA2 ........................................................................... 24
5.1.1. Mechanism................................................................................................................... 25
5.1.2. Indicaties voor een mutatieanalyse.......................................................................... 26
5.1.3. Preventieve strategie.................................................................................................. 27
5.1.4. Behandeling ................................................................................................................. 27
5.1.5. Andere borstkankergenen ......................................................................................... 29
5.2. Other cancer genes? .......................................................................................................... 29
6. Chromosomen ............................................................................................................................. 30
6.1. Inleiding ................................................................................................................................ 30
6.1.1. Benamingen................................................................................................................. 30
6.1.2. Chromosomal anomalies ........................................................................................... 31
6.1.3. Robertiaanse translocaties (EXAMEN) ................................................................... 35
6.2. FISH: Fluorescent In Situ Hybridisation ......................................................................... 38
6.3. Technieken voor prenataal onderzoek ............................................................................ 40
6.4. Algemene extra info ........................................................................................................... 43
7. Next Generation Sequencing (NGS) ....................................................................................... 44
7.1. Sanger sequencing............................................................................................................. 44
7.2. Genetische diagnostiek ..................................................................................................... 44
Algemene begrippen: (EXAMEN) ...................................................................................................... 45
7.3. Parallel sequencing ............................................................................................................ 45
8. Prenatal diagnosis and NIPD .................................................................................................... 53
8.1. Invasive procedures ........................................................................................................... 53
8.2. Non-invasive procedures ................................................................................................... 53
8.2.1. NIPT .............................................................................................................................. 55
8.2.2. Preimplantation genetic diagnosis (PGD) ............................................................... 55
9. Farmacogenetica ........................................................................................................................ 58
9.1. Algemene principes ............................................................................................................ 58
9.1.1. The right dose for the right patient. .......................................................................... 58
9.1.2. Find the right patient for the right therapy. .............................................................. 58
9.2. Metabolisatiesnelheid is genetisch bepaald ................................................................... 59
9.3. Voorbeelden ........................................................................................................................ 61
9.3.1. Abacavir (ziagen®) sensitivity ................................................................................... 61
2
, 9.3.2. Carbamazepine (Tegretol) ........................................................................................ 61
9.3.3. Azathioprine (Imuran) and Mercaptopurin (Puri-Nethol)....................................... 61
9.3.4. fluorouracil, capecitabine, tegafur ............................................................................ 62
9.4. Companion testing – precision medicine ........................................................................ 62
10. Multifactoriële aandoeningen ................................................................................................ 65
10.1. Examples ......................................................................................................................... 65
10.2. Inleiding ............................................................................................................................ 66
10.3. Discontinue variabelen ................................................................................................... 66
10.4. Multifactoriële aandoeningen ........................................................................................ 67
10.4.1. Alzheimer’s disease................................................................................................ 67
10.4.2. Type 2 diabetes....................................................................................................... 68
10.4.3. Herhalingskans ....................................................................................................... 68
10.4.4. Pylorushypertrofie ................................................................................................... 68
10.4.5. Heritabiliteit .............................................................................................................. 68
10.5. Genetische zelftests en autonomie .............................................................................. 69
3
,Ex-examenvragen
- EXAMEN
o 4 or 5 questions
o 5 multiple choice without guess correction
- PGD (preimplantation diagnostics)
o Wat is het?
o Bespreek voor- en nadelen.
- Een man met 46 XX karyotype, welk genetisch defect?
- Foto van kind met Down
o Welke aandoening?
o Welk gen defect en hoe ontstaat het?
- Pylorusstenose, meisje minder kans dan jongen dus als zus al pylorusstenose heeft,
toekomstige broer meer kans, waarom?
- 5 meerkeuze vragen zonder giscorrectie.
- Geef 2 voorbeelden van GM met hun indicaties en werkingsmechanisme gebruikt voor precision
medicine.
- Wat is exoom sequencing en wat is het voordeel in de moleculaire diagnostiek?
- Geef 3 of 4 specifieke eigenschappen van X-gebonden erfelijke aandoeningen.
- Beschrijf de factoren en situaties die incidentie en herhalingskans van multifactoriële
aandoeningen bepalen.
- Wat is de invloed van CYP2D6 op de activiteit van nortriptyline? Bespreek op niveau van DNA.
- Wat is NIPD en bespreek de voordelen ervan.
1. Inleiding
- Humane, medische, klinische, moleculaire genetica
- Constitutionele aandoeningen
- Verworven aandoeningen
- Monogene aandoeningen
- Chromosomale afwijkingen
- Multifactoriële aandoeningen
4
, 1.1. Soorten mutaties op chromosomaal niveau
1.1.1.Nonsense mutations
- No amino acids, just stopcodon
1.1.2.Missense mutations
- Amino acid is replaced
- Phylogenic inheritance: The evolution conserved the mutation
1.1.3.Splicing mutations
1.1.4.Neutral variants
- Change in codon doesn’t affect amino acids
1.1.5.Insertions/ deletions
- In frame mutations: triplet is OK
- Out of frame mutations: triplet not OK
5
