NEUROLOGICAL DISORDERS TYPICAL THINGS IN
NEUROGENETICS: INTRODUCTION
= disease CNS & PNS, so: B, spinal cord, NEURLOGICAL DISORDERS
cranial nerves, peripheral nerves, nerve II. DEMENTIAS V. PAROXYSMAL DISORDERS > multiple disease subtypes
roots, ANS, neuromuscular junction & > multiple ≠ presentations disease within
muscles AD, frontotemporal dementia (FTD), = disorder occur unexpectedly in episodes family
→ eg. Alzheimer (AD), epilepsy, cerebro- dementia with Lewy bodies (DLB) & prion → epilepsy, migraine, episodic ataxias,... > challenging diagnosis
vascular diseases,... disease
> progressive disease + no cure
→ neuro-infections, traumatic VI. NEURODEVELOPMENTAL → makes patients motivated to
disorders & neurological disorders DISORDERS participate in research
bcs of malnutrition are ≠ -> not
neurogenetic
Autism spectrum disorder, sex chromosome FACTORS SUGGESTING
aneuploidies, Fragile X syndrome,... NEUROGENETIC DISORDERS
CLASSIFICATION > disease occurring in same family
> 200 neuro disorders -> can classify in
VII. NEUROCUTANEOUS
→ but familial disorders not always
many ways (age, cells, lobes,...) DISORDERS genetic & genetic disorders not
→ some diseases fit in multiple categories benign tumours in the B, but will lead to always familial !!!! -> think about
epilepsy environmental factors
are going to see 1 classification → neurofibromatosis type 1 (NF1) & > combination certain signs & symptoms
tuberous sclerosis complex (TSC) eg. facial acne + seizures = tuberous
I. MOVEMENT DISORDERS sclerosis
2 types: VIII. CEREBROVASCULAR → neurologist trained to
→ hypokinectic = slowness movement III. DISEASES OF WM DISEASES recognize symptoms
→ hyperkinetic = excessive involuntary 2 types: > chronic & progressive disease course
> dysmyelinating = primary abnormality of diseases in the blood vessels in the B > consanguinity = parents related
movements
myelin formation (so from birth) → cerebral autosomal-dominant arterio- > ↑ frequency in specific ethnic group
Wilson disease, Parkinson, Huntington, > demyelinating = secondary destruction pathy with subcortical infarcts & leuko-
cerebellar ataxias,... normal myelin encephalopathy (CADASIL) genetic, but doesn’t look like it?
→ was present, but is destroyed > reduced penetrance
= destruction cerebellum → MS!!!! = snowflake disease: loss of IX. MAJOR ADULT > de novo mutations
→ less control over movement, speech, loss of balance,... PSYCHIATRIC DISORDERS > sometimes parents die early -> doesn’t
balance & coordination → symptoms change over time look genetic
B cells are not dying, but it’s more a > non paternity (no info about true father)
→ ≠ types: Friederichs’s (most (worse/better) disorder in the functioning of the B
common), AOA2 (rare),... → addiction, obsessive compulsive
→ some genetic, others not (B IV. NEUROMUSCULAR
disorder & bipolar disorder
injury & alcohol) DISORDERS
→ snowflake disease: ≠ for everyone affects upper & lower motor N (UMN & LMN)
+ muscles
→ facioscapulohumeral muscular dystrophy,
amyotrophic lateral sclerosis (ALS), Duchenne
muscular dystrophy,...
, look at which chr. + region disease gene is CANDIDATE GENE APPROACH POLYGENIC RISK SCORE
located
→ makes use of LOD scores (>3 = prove only test 1 gene 2 step approach:
→ very biased method, bcs you have a a) get info on population level
of linkage)
biological reason to test gene + low b) generate polygenic risk score (PRS)
statistical burden of proof (p<0,05)
FROM MONOGENIC PROBLEMS WITH LA → but works sometimes = index derived by adding up #variants
DISORDERS TO COMPLEX > sporadic diseases x effect size
> unclear inheritance pattern HAPMAP PROJECT → gives info about risk of developing
DISEASES > it’s time consuming & costly disease: high/low = high/low risk
I. MONOGENIC: clear phenotype with = catalogue of genetic variants
> reduced penetrance: have disease gene, → based on combined effects
Mendelian inheritance but no/less symptoms → contains variants of 11 populations
→ PRS generated on population level
II. OLIGOGENIC: variable phenotype + > phenocopies = phenotype looks the same → allowed design of genome-wide panels
& applied individual level
often multiple genes involved as gene of interest, but they don’t of markers for association studies
→ ONLY FOR COMMON VARIANTS
III. POLYGENIC: complex traits, multi- have disease gene
factorial & phenotypic heterogeneity GENOME-WIDE → which variants include in PRS?
> significance based (p-value
messes up linkage analysis ASSOCIATION STUDIES cutoff)
neuro disorder can present in all these ways eg. Dopa-responsive dystonia family (GWAS) > PW based
with GCH1 deletion > derived from other disease
GENE DISCOVERY → study did linkage analysis: GCH1 scanning markers across ≠ individuals to
many reasons to do genetic research: to determine overlap: see if
was not a candidate region find genetic variations associated with a diseases have influence on
> provides definitive diagnosis → new locus: DYT14 on same chr. specific disease
> understanding biology disorder each other
→ but they kept studying GCH1 → used to identify risk genes for neuro
> provides potential biomarkers disorders BURDEN ANALYSIS
& saw an rare mutation (del)
> therapeutic targets
> can give genetic counseling to family → so bcs of the phenocopy first classical GWAS performed with
the right gene was Manhatten plot used!!!! genotype array’s with common variants
excluded for candidate →dotted line = significance threshold →then exome/genome sequencing to
LINKAGE ANALYSIS (LA) gene region (p< 5 x 10-8) study rare variants
based on genetic distance (cM) & → every dot = variant → problem: lack of statistical
variant/haplotype sharing POPULATION GENETICS → only dots above line are power
→ screen entire genome significant
homogenous populations = “large families”
→ look for shared regions between burden analysis came into play
→ easy to collect unrelated patients
healthy & ill family members → groups rare variants based on
→ big problem = population stratification
biological info (don’t get this)
do this with genetic markers (400-1000):
> SNPs if control & patients are ≠ bcs of
> repeat sequences = short tandem another reason then the disease, you
repeats (STR) will find ≠ not related to disease
> mini-satellites: repeats 5bases or more
> microsatellites: repeat di-, tri- or
tetra nucleotides
> multi-allelic genotypes: 5-12 repeats
, COMMON (>1 or >5%) VS FAMILIAL ALS GENES PRS SUGGEST GENETIC MUTATIONS IN CODING
RARE (<<1) GENETIC > SOD1 = first identified → 100 ≠ dominant
OVERLAP BETWEEN ALS & SEQUENCE
MUTATIONS mutations → 1 exception p.D90A -> SHIZOPHRENIA I. MISSENSE = 1 AA changed
recessive (mostly Scandinavian population) took PRS from schizophrenia GWAS: looked for → can/cannot affect P function
> rare mutations in common disorders -> large depending on conservative or
> ALS2: recessive → juvenile ALS variants that ↑ risk schizophrenia
effects non-conservative + function AA
> C9orf72 = repeat expansion inherited → overlapped schizophrenia PRS with ALS
→ identified via LA in families: eg. II. NONSENSE: 1 AA changed -> forms
dominant → saw ↑ ALS cases compared to controls
Huntington stop codon
> common mutations -> large effect in groups with high schizophrenia PRS
most common cause repeat expansion, but → premature termination or
→ identified via LA translation
20% mutations of familial genes also found in EXOME SEQUENCING STUDY
> common variant -> small effect III. SILENT: does not change AA, but
sporadic patients
→ identified via GWAS studies & can → there’s sporadic penetrance IN ALS IDENTIFIED TBK1 can still have phenotypic effect
be combined with PRS MUTATION IV. INSERTION/DELETION = number
→ + see oligogenic basis in ALS
gene burden association study: WES in of bases that is multiple of 3
MANOLIO PLOT V. FRAMESHIFT = insertion/deletion
= multiple genes that work together to sporadic ALS patients & controls
cause ALS → identified TBK1 mutation in 1% of of number of bases not multiple of 3
→ multiple genes contributing to disease patients = rare variant → usually introduces pre STOP
causes phenotypic variability + goes VI. SPLICE SITE: changes DNA seq.
together with reduced penetrance !!! role in autophagy & neuro-inflammation at boundary exon & intron
these 3 connected TYPES OF DISEASE-CAUSING keep in mind: genes can have multiple
with each other GENETIC VARIATION transcripts
→ each transcript affected in ≠ ways
mutation classification by effect on DNA
molecule: NONSENSE MEDIATED
true, but rare variants most frequent I. SUBSTITUTION
type of variation in human genome !!! II. DELETION (can be in or out of frame) DECAY
→ find with burden analysis III. INSERT (can be in or out of frame) during splicing exon junction complexes
MOST NEURO DISEASES ENVIRONMENT & ALS IV. INVERSION = 180° rotation made on an exon-exon border
V. RECIPROKAL TRANSLOCATION: parts of
= GENETICALLY excessive sport changes expression ALS- nonhomologous chr. change places removed during 1st transcription by
HETEROGENEOUS WITH associated genes VI. CHROMOSOMAL REARRANGEMENTS: affects ribosome
→ a lot of sport = risk ALS↑ many genes at one time → when pre STOP EJC not removed
MULTIPLE MODES OF
→ signal to destroy mRNA: no P &
INHERITANCE ALS RISK GENES IDENTIFIED most !!! is outcome mutation on DNA, RNA or P less mRNA
eg. amyotrophic lateral sclerosis (ALS) THROUGH GWAS → effect will depend on if variant affects → pre STOP before last exon escape
→ UMN & LMN affected coding or non coding regions of genome NMD (<55 nucleotides before
most recent ALS-GWAS: 30.000 patients
→ 10% familial & 90% sporadic complex)
& 125.000 controls
→ can have single genes that → found 15 ALS risk loci → get shorter P & normal mRNA
cause ALS or multiple genes
