Lecture 5 - mutations + gene overview of NDDs Flashcards
How many children are affected by NDDs?
Roughly 10%
NDDs that are largely genetic
Mendelian/Monogenic
1. Developmental & Epileptic Encephalopathies
2. Fragile X syndrome
NDDs that are a even mix of genetic and environmental
Complex/Polygenic/Multifactorial
1. ADHD
2. Tics
3. ASD
NDD that is largely environmental
Cerebral Palsy
(but most have a genetic disorder)
Types of Mendelian inheritance
- Autosomal dominant + recessive
- X-linked dominant +recessive
- (very rarely) Y-linked
How many gene copies are needed to develop the disorder (Autosomal)
DOM: Only need one mutated gene to develop disorder
REC: need two mutated copies of the gene to express phenotype (disease)
X-linked dominant features
Affected father > daughter will always be affected
Affected mother > 50% chance of passing to kids
X-Linked recessive features
Males largerly affected
Daughters may be carriers
* Only have the disease if both parents have the disease (i.e. mum is not JUST a carrier)
X chromosome inactivation
may inactive the only working copy of the gene in women
De novo mutations
Can look like recessive inheritance
* ~70 de novo variants/genome
* Usually not in areas that affect gene function
Gross chromosomal abnormalities example
E.g. 3 copies chr 21 (Down syndrome)
Structural variation (genetic mutation) involves…
Whole genes/exons
Types of point mutations
- SUBstitution
- INSERTion
- DELETion
Types of effects of coding region point mutations
- Missense
- Nonsense
- Frameshift
- Synoymous
Where would the mutation leading to Mendelian/monogenic disorders typically be?
Coding region or splice sites
Nonsense variants
Stop/termination codons (e.g. Leu > Ter)
* Truncated protein OR No protein
Missense variants
Swap one AA for another (e.g. Leu > Phe)
* Maybe effect on protein function
Conservative Vs. Non-conservative missense variants
CON - AA swapped with one of similar chemical properties/structure
NON - dissimilar chemical properties/structure
Frameshift mutation
Caused by insert/delete not a multiple of 3
* premature STOP
* drastic effects
Splice-site variants
Several conserved sequences near intron/exon junction required for spliceosome binding
* Variants affecting GT…AG dinucleotides (‘essential’ splice sites) usually affect splicing
Types of splice-site variants
- Exon skipping
- Intron inclusion
- Cryptic splice site use
Developmental & Epileptic Encephalopathies (DEE)
Most severe group of epilepsies
* occurs in infancy
Clinical signs of DEE
Slowing/regression in development/cognition/behaviour + epileptiform activity on EEG.
DEE genetics
- ~50% have a mutation in a known DEE gene
- Over 900 Mendelian DEE genes found so far
- Many modes of inheritance
What types of proteins do DEE genes make?
- Voltage/ligand-gated ion channels
- Synapse proteins
- Cell signalling
- Epigenetic regulation
SCN1A and epilepsy
Missense variants found in epileptic family members
* DEE patients then screened > All had multiple types mutations at this gene
Whole-genome sequencing
Fragmentation of gDNA & high-throughput DNA sequencing technology
* Compare patient sequence to human reference sequence
Whole-exome sequencing
Enrichment of DNA for subset encoding proteins (i.e., exons) before sequencing.
* Cheaper BUT doesn’t detect structural variation, repeat expansions
Parent-child DEE trios with whole-exome sequencing data from multiple studies
Mutations in PPP3A
* Calcineurin subunit: key regulator of synaptic vesicle recycling
* Linked to phenotype, segregates with disease, other patients have it and absent from normal pop.
Fragile X syndrome (genetic mutation)
Full mutation (silencing) of FMR1 on X chromosome (milder in females)
Fragile X symptoms
Most frequent X-linked intellectual disability & monogenic form of ASD
* Severe behavioural changes, inc. hyperactivity, social anxiety; language delays, seizures
Fragile X syndrome in females
Severity correlated with degree X inactivation (random silencing of one copy of X chr in females)
FMR1 repeat
Unstable
* No. repeats can expand during DNA replication/repair
* Subsequent generations may have longer repeat length
* Intermediate → premutation
* Premutation → full mutation
Attention-deficit/hyperactivity disorder (ADHD) Symptoms
Inattention, hyperactivity, impulsivity
ADHD inheritance and prevalence
Multifactorial/polygenic disorder
* Very common: ~5% school-aged children,~2.5% young adults, ~1% older adults
* Heritability is ~80%
Genome-wide association studies (GWAS)
Examine 1-10,000,000 common SNPs distributed along each chromosome
* Compare allele frequency between cases & controls
GWAS for ADHD
27 loci significantly associated with disease:
* inc. one near PTPRF (role in synaptogenesis)
* also associated with scz, ASD, educational attainment
Autism spectrum disorder (ASD) symptoms
Social communication/interaction deficits & restricted, repetitive, stereotyped patterns of behaviors/interests, higher skills in systemizing
ASD Environmental risk factors
older parents, birth trauma, gestational diabetes, valproate
Heritability of ASD
~80%:
* Causative mutations in Mendelian genes (<10% ASD)
* Rare point mutations/copy-number variants with large effect (~10-20% ASD) – synaptic proteins (eg NRXN1, SHANK3, SYNGAP1)
* Common variants with small effect
