Neurogenetics
Always keep the lecture slides
next to this summary so you
HC 1 – Introduction. can also see the visuals and
extra details.
Neurological disorder = Diseases of the central and peripheral nervous system.
Ê Many classification systems exist, based on:
- Clinical presentation
- Primary affected cell type or brain region
- Temporal expression
Classification of neurological disorders
1) Movement disorders
Ê Cerebellum is defect -> affecting ability to control movements.
Ê Movement affected by 2 ways:
- Hypokinetic disorders → too slow movements
- Hyperkinetic disorders → excessive involuntary movements
Ê Examples:
- Cerebellar ataxias
- Parkinson Disease (PD)
- Huntington’s disease
2) Dementias
= an umbrella term for a collection of diseases and their symptoms, including memory loss, impaired judgment, personality
changes and inability to perform daily activities.
Ê Examples:
- Alzheimer disease (AD)
- Frontotemporal dementia (FTD)
- Dementia with Lewy bodies (DLB)
- Prion disease
3) Diseases of white matter
Ê White matter in the brains is affected → resulting in white matter lesions = can happen primarily or secondary:
- Dysmyelinating = primary abnormality of myelin formation → myelin not correctly formed
- Demyelinating = secondary destruction of normal myelin → myelin formed normal but afterwards destructed
Ê Examples:
- Alexander disease
- Multiple sclerosis ( = demyelinating disease)
4) Neuromuscular disorders
Ê Caused by affected upper and lower motor neurons and neuromuscular junction
Ê Examples:
- Facioscapulohumeral muscular dystrophy (FSHD)
- Spinal muscular atrophy (SMA)
- Amyotrophic lateral sclerosis (ALS)
- Neuropathy
- Duchenne muscular dystrophy
5) Paroxysmal disorders
Ê Disorders that occur unexpectedly in episodes
Ê Examples:
- Epilepsy
- Migraine
6) Neurodevelopmental disorders
Ê Arise from abnormal brain development or function
Ê Examples:
- Autism spectrum disorder
- Tourette disorder and other tic disorders
- Fragile X syndrome
,7) Neurocutaneous disorders (phakomatoses)
= Characterized by abnormal development of cells in the skin, brain and spinal cord.
• Because the skin and nervous system come from the same embryonic tissue (the ectoderm), mutations in certain
genes can cause abnormalities in both.
Ê They often result in non-malignant tumors or lesions, spread over whole body
Ê The patients will not die due to the tumors but struggle with disabilities, mental retardation,...
Ê Example: Neurofibromatosis type 1 (NF1) -> characterized with café-au-lait spots
8) Cerebrovascular diseases
Ê In these diseases the blood vessels in the brain will be affected causing neurological disorders
Ê Example: CADASIL
9) Major adult psychiatric disorders
- Addiction
- Obsessive compulsive disorder
- Bipolar disorder
Factors suggesting a neurogenetic disorder
=> How do we identify a neurogenetic disorder?
1. A positive family history of the same or a similar neurological disorder
Ê You see the disease in every generation
Ê !!!! Familial disorders aren’t always genetic + genetic disorders aren’t always familial
9 Reasons why a familial disorder isn’t genetic:
• Environmental factors → e.g. local food
• Common late-onset neurological conditions → e.g., dementia: people over 80 have a higher chance
• Sporadic cases:
- Recessive gene → Disease only shows if a person inherits two copies of the affected gene.
- Multifactorial diseases → Not a single gene mutation, but several risk factors acting together.
- Reduced penetrance → Some individuals have the disease-causing gene but remain unaffected.
- De novo mutations → New mutation that is not inherited from parents, but child can pass it on.
2. A constellation of signs and symptoms suggesting a known genetic syndrome
Ê Example: epilepsy + facial acne = tuberous sclerosis
3. Subtle onset with chronic, progressive clinical course
4. Consanguinity -> patients that are related
5. Increased frequency of a disease in a specific ethnic group
Inheritance patterns in neurological disorders
Autosomal dominant
- Males and females are equally affected
- Every affected individual has at least one affected parent
- Two affected individuals may have unaffected children
- Phenotype generally appears in every generation
- Affected individuals mating with unaffected individuals have at least 50%
chance of transmitting the trait to each child.
Autosomal recessive
- Males and females are equally affected
- Affected individual may have unaffected parents
- All children of two affected individuals are affected
- Phenotype may skip a generation
,X-linked dominant
- Trait is never passed from father to son
- All daughters of an affected male and a normal female are affected
- Females are more likely to be affected than males
- Examples: Fragile X syndrome
X-linked recessive
- Trait is never passed from father to son
- Males more likely to be affected than females
- Trait or disease typically passed from an affected grandfather, through
carrier daughters, to half of his grandsons
- Example: Duchenne muscular dystrophy
=> See examples in HC !!!!
Most patients/families affected by neurological disorders do not have clear inheritance patterns !
Ê Even in families with monogenic disease, inheritance patterns may be unclear.
Ê Several reasons why a genetic disease will not have a clear inheritance pattern:
- Incomplete family information
- Early death
- Non-paternity
- Reduced penetrance: some individuals who carry the disease gene may stay unaffected
From monogenetic disorders to complex diseases
â Monogenic
- Disease is caused by one single gene
- Distinct phenotype
- Mendelian inheritance
- Do they really exist? → most diseases are not monogenic and there are other factors involved
â Oligogenic
- Disease caused by a small number of genes, each having a significant effect.
- Variable phenotype
â Polygenic
- Disease is caused by many genes, each contributing a small effect, often interacting with environmental factors.
- Complex traits
- Multifactorial disease
- Extensive phenotypic heterogeneity
9 = individuals with the same genotype can exhibit different observable traits or characteristics.
Ê In oligogenic and polygenetic diseases, multiple genes contribute to the development of the condition. The interaction
between these genes can influence whether the disease manifests and how severe it is. This leads to reduced
penetrance, where an individual may carry disease-associated mutations but not show symptoms, depending on the
combination of other genetic factors or environmental influences. These complex interactions also contribute to
phenotypic heterogeneity, where individuals with the same diagnosis may present with different symptoms or severity
due to varying combinations of mutations across the involved genes.
Gene identification methods
Linkage analysis
Linkage analysis uses inheritance patterns within families and genetic markers (STR or microsatellites) to map recombination’s
and locate shared chromosome regions likely containing the disease gene, with the statistical probability of the association
measured by the LOD score, followed by sequencing to pinpoint the exact gene or mutation.
Ê This is powerful for rare, high-penetrance variants.
, Caveats or issues of linkage analysis:
â Reduced penetrance: some individuals who carry the disease gene may stay unaffected
â Phenocopy = an individual with the exact same phenotype as the rest of the family but does not carry the disease-causing
gene, present in the other affected individuals.
4 When you don’t of large families => population genetics:
- Homogeneous populations act as ‘large families’
- Easier to collect many ‘unrelated’ patients
GWAS - Genome-wide association study
GWAS compares large groups of patients and controls to identify common genetic variants (SNPs) that occur more frequently
in affected individuals and can be used to identify risk genes for neurological disorders.
Manhattan plot
Results are often visualized in a Manhattan plot, where each dot represents a single
variant, the X-axis shows chromosomes, and the Y-axis shows the p-value. Because millions
of variants are analyzed, the threshold for significance is usually p < 5x10⁻⁸, represented
by a dotted line; all points above this line indicate loci where genetic variants are more
frequent in cases and are therefore risk factors for the disease.
Caveat or issue with population genetics and thus GWAS:
â Population stratification = systematic ancestry differences between patients and controls.
Ê Example: patients from Europe and controls from Africa
Polygenetic risk score
In association studies (GWAS), each common genetic variant typically has a small individual effect. To better assess genetic
risk, researchers combine these effects (combined effect) into a single score, a polygenic risk score (PRS).
The process begins with a case-control association study at the population level, where the effect size of each variant is
determined. Once these effect sizes are established, the PRS can be calculated for individuals. This is done by summing the
weighted contributions of each variant present in a person’s genome, based on the effect sizes derived from the population
study. So, the polygenic risk score is first generated using population-level data and then applied at the individual level to
estimate genetic risk.
Burden analysis
What about rare variants?
Exome or genome sequencing can be used to study rare genetic variants. However, in most cases, individual rare variants cannot
be analyzed separately due to insufficient statistical power.
Ê To address this, researchers use the concept of burden analysis, which groups rare variants based on biological
information to test their combined effect on disease risk or phenotype.
Contribution of common and rare variants
Manolio plot
A Manolio plot is a way to visualize the relationship between allele frequency (how common a variant is in the population)
and effect size (the strength of its impact on disease risk).
• Y-axis = effect size (from low to high)
• X-axis = allele frequency (from very rare to common variants)
â Linkage analysis → rare, high-effect mutations (familial).
â GWAS → common, low-effect variants (population level).
â Burden analysis → rare, low-effect variants
Always keep the lecture slides
next to this summary so you
HC 1 – Introduction. can also see the visuals and
extra details.
Neurological disorder = Diseases of the central and peripheral nervous system.
Ê Many classification systems exist, based on:
- Clinical presentation
- Primary affected cell type or brain region
- Temporal expression
Classification of neurological disorders
1) Movement disorders
Ê Cerebellum is defect -> affecting ability to control movements.
Ê Movement affected by 2 ways:
- Hypokinetic disorders → too slow movements
- Hyperkinetic disorders → excessive involuntary movements
Ê Examples:
- Cerebellar ataxias
- Parkinson Disease (PD)
- Huntington’s disease
2) Dementias
= an umbrella term for a collection of diseases and their symptoms, including memory loss, impaired judgment, personality
changes and inability to perform daily activities.
Ê Examples:
- Alzheimer disease (AD)
- Frontotemporal dementia (FTD)
- Dementia with Lewy bodies (DLB)
- Prion disease
3) Diseases of white matter
Ê White matter in the brains is affected → resulting in white matter lesions = can happen primarily or secondary:
- Dysmyelinating = primary abnormality of myelin formation → myelin not correctly formed
- Demyelinating = secondary destruction of normal myelin → myelin formed normal but afterwards destructed
Ê Examples:
- Alexander disease
- Multiple sclerosis ( = demyelinating disease)
4) Neuromuscular disorders
Ê Caused by affected upper and lower motor neurons and neuromuscular junction
Ê Examples:
- Facioscapulohumeral muscular dystrophy (FSHD)
- Spinal muscular atrophy (SMA)
- Amyotrophic lateral sclerosis (ALS)
- Neuropathy
- Duchenne muscular dystrophy
5) Paroxysmal disorders
Ê Disorders that occur unexpectedly in episodes
Ê Examples:
- Epilepsy
- Migraine
6) Neurodevelopmental disorders
Ê Arise from abnormal brain development or function
Ê Examples:
- Autism spectrum disorder
- Tourette disorder and other tic disorders
- Fragile X syndrome
,7) Neurocutaneous disorders (phakomatoses)
= Characterized by abnormal development of cells in the skin, brain and spinal cord.
• Because the skin and nervous system come from the same embryonic tissue (the ectoderm), mutations in certain
genes can cause abnormalities in both.
Ê They often result in non-malignant tumors or lesions, spread over whole body
Ê The patients will not die due to the tumors but struggle with disabilities, mental retardation,...
Ê Example: Neurofibromatosis type 1 (NF1) -> characterized with café-au-lait spots
8) Cerebrovascular diseases
Ê In these diseases the blood vessels in the brain will be affected causing neurological disorders
Ê Example: CADASIL
9) Major adult psychiatric disorders
- Addiction
- Obsessive compulsive disorder
- Bipolar disorder
Factors suggesting a neurogenetic disorder
=> How do we identify a neurogenetic disorder?
1. A positive family history of the same or a similar neurological disorder
Ê You see the disease in every generation
Ê !!!! Familial disorders aren’t always genetic + genetic disorders aren’t always familial
9 Reasons why a familial disorder isn’t genetic:
• Environmental factors → e.g. local food
• Common late-onset neurological conditions → e.g., dementia: people over 80 have a higher chance
• Sporadic cases:
- Recessive gene → Disease only shows if a person inherits two copies of the affected gene.
- Multifactorial diseases → Not a single gene mutation, but several risk factors acting together.
- Reduced penetrance → Some individuals have the disease-causing gene but remain unaffected.
- De novo mutations → New mutation that is not inherited from parents, but child can pass it on.
2. A constellation of signs and symptoms suggesting a known genetic syndrome
Ê Example: epilepsy + facial acne = tuberous sclerosis
3. Subtle onset with chronic, progressive clinical course
4. Consanguinity -> patients that are related
5. Increased frequency of a disease in a specific ethnic group
Inheritance patterns in neurological disorders
Autosomal dominant
- Males and females are equally affected
- Every affected individual has at least one affected parent
- Two affected individuals may have unaffected children
- Phenotype generally appears in every generation
- Affected individuals mating with unaffected individuals have at least 50%
chance of transmitting the trait to each child.
Autosomal recessive
- Males and females are equally affected
- Affected individual may have unaffected parents
- All children of two affected individuals are affected
- Phenotype may skip a generation
,X-linked dominant
- Trait is never passed from father to son
- All daughters of an affected male and a normal female are affected
- Females are more likely to be affected than males
- Examples: Fragile X syndrome
X-linked recessive
- Trait is never passed from father to son
- Males more likely to be affected than females
- Trait or disease typically passed from an affected grandfather, through
carrier daughters, to half of his grandsons
- Example: Duchenne muscular dystrophy
=> See examples in HC !!!!
Most patients/families affected by neurological disorders do not have clear inheritance patterns !
Ê Even in families with monogenic disease, inheritance patterns may be unclear.
Ê Several reasons why a genetic disease will not have a clear inheritance pattern:
- Incomplete family information
- Early death
- Non-paternity
- Reduced penetrance: some individuals who carry the disease gene may stay unaffected
From monogenetic disorders to complex diseases
â Monogenic
- Disease is caused by one single gene
- Distinct phenotype
- Mendelian inheritance
- Do they really exist? → most diseases are not monogenic and there are other factors involved
â Oligogenic
- Disease caused by a small number of genes, each having a significant effect.
- Variable phenotype
â Polygenic
- Disease is caused by many genes, each contributing a small effect, often interacting with environmental factors.
- Complex traits
- Multifactorial disease
- Extensive phenotypic heterogeneity
9 = individuals with the same genotype can exhibit different observable traits or characteristics.
Ê In oligogenic and polygenetic diseases, multiple genes contribute to the development of the condition. The interaction
between these genes can influence whether the disease manifests and how severe it is. This leads to reduced
penetrance, where an individual may carry disease-associated mutations but not show symptoms, depending on the
combination of other genetic factors or environmental influences. These complex interactions also contribute to
phenotypic heterogeneity, where individuals with the same diagnosis may present with different symptoms or severity
due to varying combinations of mutations across the involved genes.
Gene identification methods
Linkage analysis
Linkage analysis uses inheritance patterns within families and genetic markers (STR or microsatellites) to map recombination’s
and locate shared chromosome regions likely containing the disease gene, with the statistical probability of the association
measured by the LOD score, followed by sequencing to pinpoint the exact gene or mutation.
Ê This is powerful for rare, high-penetrance variants.
, Caveats or issues of linkage analysis:
â Reduced penetrance: some individuals who carry the disease gene may stay unaffected
â Phenocopy = an individual with the exact same phenotype as the rest of the family but does not carry the disease-causing
gene, present in the other affected individuals.
4 When you don’t of large families => population genetics:
- Homogeneous populations act as ‘large families’
- Easier to collect many ‘unrelated’ patients
GWAS - Genome-wide association study
GWAS compares large groups of patients and controls to identify common genetic variants (SNPs) that occur more frequently
in affected individuals and can be used to identify risk genes for neurological disorders.
Manhattan plot
Results are often visualized in a Manhattan plot, where each dot represents a single
variant, the X-axis shows chromosomes, and the Y-axis shows the p-value. Because millions
of variants are analyzed, the threshold for significance is usually p < 5x10⁻⁸, represented
by a dotted line; all points above this line indicate loci where genetic variants are more
frequent in cases and are therefore risk factors for the disease.
Caveat or issue with population genetics and thus GWAS:
â Population stratification = systematic ancestry differences between patients and controls.
Ê Example: patients from Europe and controls from Africa
Polygenetic risk score
In association studies (GWAS), each common genetic variant typically has a small individual effect. To better assess genetic
risk, researchers combine these effects (combined effect) into a single score, a polygenic risk score (PRS).
The process begins with a case-control association study at the population level, where the effect size of each variant is
determined. Once these effect sizes are established, the PRS can be calculated for individuals. This is done by summing the
weighted contributions of each variant present in a person’s genome, based on the effect sizes derived from the population
study. So, the polygenic risk score is first generated using population-level data and then applied at the individual level to
estimate genetic risk.
Burden analysis
What about rare variants?
Exome or genome sequencing can be used to study rare genetic variants. However, in most cases, individual rare variants cannot
be analyzed separately due to insufficient statistical power.
Ê To address this, researchers use the concept of burden analysis, which groups rare variants based on biological
information to test their combined effect on disease risk or phenotype.
Contribution of common and rare variants
Manolio plot
A Manolio plot is a way to visualize the relationship between allele frequency (how common a variant is in the population)
and effect size (the strength of its impact on disease risk).
• Y-axis = effect size (from low to high)
• X-axis = allele frequency (from very rare to common variants)
â Linkage analysis → rare, high-effect mutations (familial).
â GWAS → common, low-effect variants (population level).
â Burden analysis → rare, low-effect variants
