Con ten ts
01 Introduction clinical genetics
02 Organization of rare disease healthcare
03 Hedgehog pathway in human malformation
04 Introduction to personalized medicine
05 Introduction biomarkers and medicines
06 Biomarker development in neurological diseases
07 AI for biomarker discovery
08 Introduction to the track “imaging” (not exam)
09 Radiology (not exam)
10 Artificial intelligence applied to medicine
11 Computer-assisted surgery for personalized medicine
12 Imaging, radiomics, and multidisciplinary
13 Personalized treatment of abdominal aortic aneurysms (AAA)
14 Biobusiness
15 Self-directed learning (no exam material)
16 In vitro models for bone remodeling investigating loading on bone
17 Emma center for personalized medicine
18 Novel treatments for metabolic cardiomyopathy
19 Therapeutic development for rare chronic intestinal diseases
20 Human brain model systems (6 on the wheel)
21 Inherited metabolic diseases: overview of personalized therapies
22 Cystinosis as a prototype disease for personalized medicine
23 Trial design to deliver therapies for rare diseases
24 Genetic obesity disorders: from diagnosis to treatment
25 Cantu syndrome
26 Stable isotope technology (not exam)
27 Neurodevelopmental precision and personalization
28 CRISPR strategies to develop and accelerate therapies for rare diseases
29 Personalized medicine for chronic viral infections
Personalized Medicine · study summary
, lecture 01
Intr oduction clinical genetics
Personalized Medicine
A disorder is rare when less than 1 per 2000 people are affected. 1 in 17 people in NL have a form of a rare
disease, of which 80% is genetic. In personalized medicine, we want to apply the genetic insights in individual
cases of patients.
Major subjects in clinical genetics
Oncogenictics (e.g. hereditary breast and colon cancer)
Dysmorphology/syndromes
Prenatal diagnsosis/counseling
Ultrasound abnormalities
Familial hereditary disorder
Chromosomal abnormalities
Cardiogenetics (HCM, ARVC, NCCM)
Connective tissue disorders (e.g. osteogenesis imperfecta)
Neurogenetics (e.g. Huntington’s)
What kind of questions
What is the diagnoses/syndrome?
Pregnancy related
Recurrence risk of familial disorders
Chromosomal abnormalities
Related to own health
Risk for hereditary diseases later in life (e.g. huntington)
Increased risk cancer
Increased risk sudden cardiac death
Related to future offspring
Consanguinity
Increased risk based on ethnic background.
Referral children (why do people go to the clinic)
Intellectual disability (can be isolated or with comorbidities)
Multiple congenital abnormalities
Dysmorphism (an abnormally shaped body part)
Single congenital abnormalities (e.g. cleft lip)
Hearing loss, congenital cataract
(extreme) abnormal growth (e.g. short stature, obesity)
Working flow
45-60 mins per patient for intake
Focus on complaints of patients/parents.
Check other medical history.
Ask about family history.
Do a physical examination.
Conclusion on what is going on > lab work or imaging or DNA test based on the diagnosis.
Results
Genotype-phenotype > does change in DNA explain difference in phenotype
Meaning for patient (e.g. therapeutic or more personalized care)
Personalized Medicine · study summary
,Dysmorphologies
Describing what you see. Doesn’t mean you have a certain syndrome.
Normal/variant/dysmorphism.
Terminology is important.
Pattern of recognition changes over the years. Combination of things you see in syndromes.
E.g. Down syndrome. 3 characteristics (doesn’t always mean DS, but should be in diagnosis)
Epicanthic folds (eye)
Four finger line
Sandal gap
Daan (example)
Pulmonary stenosis. Pulmonary artery has become smaller. Found in different diseases/syndromes.
Would think of different syndromes based on this. When seeing the kid, focus on different dysmorphology
patterns to make an actual diagnosis. E.g. Williams, Alagille Noonan and LEOPARD syndrome.
Daan also has short stature. Dysmorphism?
See pigmentation on the skin, nose is quite wide, ears are wider, eyes are a bit droopy. Probably will have
Noonan syndrome.
What is the value of diagnosis
Answer to parents of what they’ve been struggling with feeling of relief.
No need to investigate other causes
Often can get treatment
Information on prognosis.
Case 1
A 46-year old women has faced challenges from a young age. She started special education at age 6 and has
struggled with obesity since she was 18. Described as ‘jerky’ with frequent falls, she no longer participates in
activities.
We suspect Prader-Willi syndrome, which often includes developmental delays, motor issues, and obesity.
After genetic testing, we find a mutation that causes Coffin-Lowry syndrome. Patients with this disease can
experience SIDE (stimuli-induced drop episodes). Receiving a diagnosis makes sure we can take
preventative measures (avoid stimuli), understand the patient better, and treat the condition with
medication.
Case 2
A child presents with several concerning symptoms, including failure to thrive, cyclic vomiting, developmental
delay, seizures, and stereotypic behavior. They also exhibit autistic behavior. His genetic profiles seems to be
normal. It was thought the kid had Bohring Opitz syndrome, but his ASXL1 is normal.
WES shows a de novo fs ASXL3 mutation. This is very rare. Only recently described. Very little information
is available. This mutation is associated with a phenotype with similarities to Bohring Optiz syndrome.
Role of social media
Connects parents. Parental contact on daily life issues, questions, etc. May also induce fear or worries.
Consanguinity
In a child with consanguineous parents with a AR condition you expect a homozygous variant. Reproductive
options:
Personalized Medicine · study summary
, Deciding not to have (more) children
Accepting the risk
Adoption/sperm or egg donor
Termination of pregnancy
Pre-implantation genetic testing (PGT)
PCR
Polymerase chain reaction is the (exponential) amplification of a specific target piece of DNA. It is done in 3 steps:
Denaturation of the template into single strands.
Annealing (recombining in the double-stranded form) of primers to each original strand.
Extension of the new DNA strands from the primers.
Can be used to detect bacteria or viruses, diagnose genetic disorders or forensic investigations.
+ Simple and quick, sensitive (a very small template can be detected), specific (can differentiate genetic
samples that differ one nucleotide).
- Need to be specific, can sequence the whole genome. Cost and complexity (requires expert and can be
expensive). False positives due to contamination of primer DNA.
Sanger Sequencing
Used to determine the precise order of the nucleotides of a given DNA fragment.
Restriction enzymes (molecular scissors) cleave the DNA at sequence-specific sites.
Gel electrophoresis is used to separate DNA fragments based on their size and charge.
Smaller places move faster and go further.
Used for familial variations (passed from parent to child). The focus is on a specific gene that is associated with a
known mutation and disease.
+ cheap, 99% accurate.
- only short regions of the genome can be analyzed.
Microarrays
Nucleic acid probes can be labeled and use to detect/visualize DNA fragments.
Analysis of genomic gains and losses by array comparative genomic hybridization (aCGH).
Analysis of DNA variation for mutation detection and single nucleotide polymorphism (SNP arrays).
Analysis of differential gene expression (mRNA -> cDNA)
Can be used to study gene expression (in cancer research), drug response, development (detecting changes in
gene expression), and karyotyping.
+ Reliable, cost-effective, reproducible.
- Doesn’t provide information on position in the genome or structural information, aCGH arrays can detect
small SNPs, SNP array only covers a small region, unable to detect unknown sequences.
Next generation sequencing / whole exome sequencing
To determine DNA sequence and alterations. Used for prevention, diagnostics, targeted therapies, personalized
medicine.
Sample preparation filter on specific genes
Cluster formation
Sequencing
Data analysis
+ Broad genetic screening, improves the likelihood of identifying the responsible mutation.
- Exomes are only 2% of the whole DNA. Clinical interpretation can be difficult. Cant detect structural variations.
Expensive.
Variant classification
Disease/gene specific information. 5 possible classifications:
Benign, likely benign -> Does not contribute to disease.
Personalized Medicine · study summary
01 Introduction clinical genetics
02 Organization of rare disease healthcare
03 Hedgehog pathway in human malformation
04 Introduction to personalized medicine
05 Introduction biomarkers and medicines
06 Biomarker development in neurological diseases
07 AI for biomarker discovery
08 Introduction to the track “imaging” (not exam)
09 Radiology (not exam)
10 Artificial intelligence applied to medicine
11 Computer-assisted surgery for personalized medicine
12 Imaging, radiomics, and multidisciplinary
13 Personalized treatment of abdominal aortic aneurysms (AAA)
14 Biobusiness
15 Self-directed learning (no exam material)
16 In vitro models for bone remodeling investigating loading on bone
17 Emma center for personalized medicine
18 Novel treatments for metabolic cardiomyopathy
19 Therapeutic development for rare chronic intestinal diseases
20 Human brain model systems (6 on the wheel)
21 Inherited metabolic diseases: overview of personalized therapies
22 Cystinosis as a prototype disease for personalized medicine
23 Trial design to deliver therapies for rare diseases
24 Genetic obesity disorders: from diagnosis to treatment
25 Cantu syndrome
26 Stable isotope technology (not exam)
27 Neurodevelopmental precision and personalization
28 CRISPR strategies to develop and accelerate therapies for rare diseases
29 Personalized medicine for chronic viral infections
Personalized Medicine · study summary
, lecture 01
Intr oduction clinical genetics
Personalized Medicine
A disorder is rare when less than 1 per 2000 people are affected. 1 in 17 people in NL have a form of a rare
disease, of which 80% is genetic. In personalized medicine, we want to apply the genetic insights in individual
cases of patients.
Major subjects in clinical genetics
Oncogenictics (e.g. hereditary breast and colon cancer)
Dysmorphology/syndromes
Prenatal diagnsosis/counseling
Ultrasound abnormalities
Familial hereditary disorder
Chromosomal abnormalities
Cardiogenetics (HCM, ARVC, NCCM)
Connective tissue disorders (e.g. osteogenesis imperfecta)
Neurogenetics (e.g. Huntington’s)
What kind of questions
What is the diagnoses/syndrome?
Pregnancy related
Recurrence risk of familial disorders
Chromosomal abnormalities
Related to own health
Risk for hereditary diseases later in life (e.g. huntington)
Increased risk cancer
Increased risk sudden cardiac death
Related to future offspring
Consanguinity
Increased risk based on ethnic background.
Referral children (why do people go to the clinic)
Intellectual disability (can be isolated or with comorbidities)
Multiple congenital abnormalities
Dysmorphism (an abnormally shaped body part)
Single congenital abnormalities (e.g. cleft lip)
Hearing loss, congenital cataract
(extreme) abnormal growth (e.g. short stature, obesity)
Working flow
45-60 mins per patient for intake
Focus on complaints of patients/parents.
Check other medical history.
Ask about family history.
Do a physical examination.
Conclusion on what is going on > lab work or imaging or DNA test based on the diagnosis.
Results
Genotype-phenotype > does change in DNA explain difference in phenotype
Meaning for patient (e.g. therapeutic or more personalized care)
Personalized Medicine · study summary
,Dysmorphologies
Describing what you see. Doesn’t mean you have a certain syndrome.
Normal/variant/dysmorphism.
Terminology is important.
Pattern of recognition changes over the years. Combination of things you see in syndromes.
E.g. Down syndrome. 3 characteristics (doesn’t always mean DS, but should be in diagnosis)
Epicanthic folds (eye)
Four finger line
Sandal gap
Daan (example)
Pulmonary stenosis. Pulmonary artery has become smaller. Found in different diseases/syndromes.
Would think of different syndromes based on this. When seeing the kid, focus on different dysmorphology
patterns to make an actual diagnosis. E.g. Williams, Alagille Noonan and LEOPARD syndrome.
Daan also has short stature. Dysmorphism?
See pigmentation on the skin, nose is quite wide, ears are wider, eyes are a bit droopy. Probably will have
Noonan syndrome.
What is the value of diagnosis
Answer to parents of what they’ve been struggling with feeling of relief.
No need to investigate other causes
Often can get treatment
Information on prognosis.
Case 1
A 46-year old women has faced challenges from a young age. She started special education at age 6 and has
struggled with obesity since she was 18. Described as ‘jerky’ with frequent falls, she no longer participates in
activities.
We suspect Prader-Willi syndrome, which often includes developmental delays, motor issues, and obesity.
After genetic testing, we find a mutation that causes Coffin-Lowry syndrome. Patients with this disease can
experience SIDE (stimuli-induced drop episodes). Receiving a diagnosis makes sure we can take
preventative measures (avoid stimuli), understand the patient better, and treat the condition with
medication.
Case 2
A child presents with several concerning symptoms, including failure to thrive, cyclic vomiting, developmental
delay, seizures, and stereotypic behavior. They also exhibit autistic behavior. His genetic profiles seems to be
normal. It was thought the kid had Bohring Opitz syndrome, but his ASXL1 is normal.
WES shows a de novo fs ASXL3 mutation. This is very rare. Only recently described. Very little information
is available. This mutation is associated with a phenotype with similarities to Bohring Optiz syndrome.
Role of social media
Connects parents. Parental contact on daily life issues, questions, etc. May also induce fear or worries.
Consanguinity
In a child with consanguineous parents with a AR condition you expect a homozygous variant. Reproductive
options:
Personalized Medicine · study summary
, Deciding not to have (more) children
Accepting the risk
Adoption/sperm or egg donor
Termination of pregnancy
Pre-implantation genetic testing (PGT)
PCR
Polymerase chain reaction is the (exponential) amplification of a specific target piece of DNA. It is done in 3 steps:
Denaturation of the template into single strands.
Annealing (recombining in the double-stranded form) of primers to each original strand.
Extension of the new DNA strands from the primers.
Can be used to detect bacteria or viruses, diagnose genetic disorders or forensic investigations.
+ Simple and quick, sensitive (a very small template can be detected), specific (can differentiate genetic
samples that differ one nucleotide).
- Need to be specific, can sequence the whole genome. Cost and complexity (requires expert and can be
expensive). False positives due to contamination of primer DNA.
Sanger Sequencing
Used to determine the precise order of the nucleotides of a given DNA fragment.
Restriction enzymes (molecular scissors) cleave the DNA at sequence-specific sites.
Gel electrophoresis is used to separate DNA fragments based on their size and charge.
Smaller places move faster and go further.
Used for familial variations (passed from parent to child). The focus is on a specific gene that is associated with a
known mutation and disease.
+ cheap, 99% accurate.
- only short regions of the genome can be analyzed.
Microarrays
Nucleic acid probes can be labeled and use to detect/visualize DNA fragments.
Analysis of genomic gains and losses by array comparative genomic hybridization (aCGH).
Analysis of DNA variation for mutation detection and single nucleotide polymorphism (SNP arrays).
Analysis of differential gene expression (mRNA -> cDNA)
Can be used to study gene expression (in cancer research), drug response, development (detecting changes in
gene expression), and karyotyping.
+ Reliable, cost-effective, reproducible.
- Doesn’t provide information on position in the genome or structural information, aCGH arrays can detect
small SNPs, SNP array only covers a small region, unable to detect unknown sequences.
Next generation sequencing / whole exome sequencing
To determine DNA sequence and alterations. Used for prevention, diagnostics, targeted therapies, personalized
medicine.
Sample preparation filter on specific genes
Cluster formation
Sequencing
Data analysis
+ Broad genetic screening, improves the likelihood of identifying the responsible mutation.
- Exomes are only 2% of the whole DNA. Clinical interpretation can be difficult. Cant detect structural variations.
Expensive.
Variant classification
Disease/gene specific information. 5 possible classifications:
Benign, likely benign -> Does not contribute to disease.
Personalized Medicine · study summary
