Lecture 5 - mutations + gene overview of NDDs

Question 1

How many children are affected by NDDs?

Answer 1

Roughly 10%

Question 2

NDDs that are largely genetic

Answer 2

Mendelian/Monogenic
1. Developmental & Epileptic Encephalopathies
2. Fragile X syndrome

Question 3

NDDs that are a even mix of genetic and environmental

Answer 3

Complex/Polygenic/Multifactorial
1. ADHD
2. Tics
3. ASD

Question 4

NDD that is largely environmental

Answer 4

Cerebral Palsy
(but most have a genetic disorder)

Question 5

Types of Mendelian inheritance

Answer 5

• Autosomal dominant + recessive
• X-linked dominant +recessive
• (very rarely) Y-linked

Question 6

How many gene copies are needed to develop the disorder (Autosomal)

Answer 6

DOM: Only need one mutated gene to develop disorder
REC: need two mutated copies of the gene to express phenotype (disease)

Question 7

X-linked dominant features

Answer 7

Affected father > daughter will always be affected
Affected mother > 50% chance of passing to kids

Question 8

X-Linked recessive features

Answer 8

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)

Question 9

X chromosome inactivation

Answer 9

may inactive the only working copy of the gene in women

Question 10

De novo mutations

Answer 10

Can look like recessive inheritance
* ~70 de novo variants/genome
* Usually not in areas that affect gene function

Question 11

Gross chromosomal abnormalities example

Answer 11

E.g. 3 copies chr 21 (Down syndrome)

Question 12

Structural variation (genetic mutation) involves…

Answer 12

Whole genes/exons

Question 13

Types of point mutations

Answer 13

1. SUBstitution
2. INSERTion
3. DELETion

Question 14

Types of effects of coding region point mutations

Answer 14

1. Missense
2. Nonsense
3. Frameshift
4. Synoymous

Question 15

Where would the mutation leading to Mendelian/monogenic disorders typically be?

Answer 15

Coding region or splice sites

Question 16

Nonsense variants

Answer 16

Stop/termination codons (e.g. Leu > Ter)
* Truncated protein OR No protein

Question 17

Missense variants

Answer 17

Swap one AA for another (e.g. Leu > Phe)
* Maybe effect on protein function

Question 18

Conservative Vs. Non-conservative missense variants

Answer 18

CON - AA swapped with one of similar chemical properties/structure

NON - dissimilar chemical properties/structure

Question 19

Frameshift mutation

Answer 19

Caused by insert/delete not a multiple of 3
* premature STOP
* drastic effects

Question 20

Splice-site variants

Answer 20

Several conserved sequences near intron/exon junction required for spliceosome binding
* Variants affecting GT…AG dinucleotides (‘essential’ splice sites) usually affect splicing

Question 21

Types of splice-site variants

Answer 21

1. Exon skipping
2. Intron inclusion
3. Cryptic splice site use

Question 22

Developmental & Epileptic Encephalopathies (DEE)

Answer 22

Most severe group of epilepsies
* occurs in infancy

Question 23

Clinical signs of DEE

Answer 23

Slowing/regression in development/cognition/behaviour + epileptiform activity on EEG.

Question 24

DEE genetics

Answer 24

• ~50% have a mutation in a known DEE gene
• Over 900 Mendelian DEE genes found so far
• Many modes of inheritance

Question 25

What types of proteins do DEE genes make?

Answer 25

* **Voltage/ligand**-gated ion channels * **Synapse** proteins * Cell **signalling** * **Epigenetic** *regulation*

Question 26

SCN1A and epilepsy

Answer 26

**Missense** variants found in epileptic family members * **DEE** patients then screened > **All** had *multiple* types **mutations** at this gene

Question 27

Whole-genome sequencing

Answer 27

***Fragmentation*** of *gDNA* & high-throughput DNA sequencing technology * Compare **patient** sequence to **human reference** sequence

Question 28

Whole-exome sequencing

Answer 28

*Enrichment* of DNA for ***subset encoding proteins*** (i.e., exons) before sequencing. * **Cheaper** BUT doesn’t detect structural variation, repeat expansions

Question 29

Parent-child DEE trios with whole-exome sequencing data from multiple studies

Answer 29

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.

Question 30

Fragile X syndrome (genetic mutation)

Answer 30

Full mutation (***silencing***) of **FMR1** on **X** chromosome (*milder* in **females**)

Question 31

Fragile X symptoms

Answer 31

Most ***frequent*** X-linked intellectual disability & **monogenic** form of **ASD** * Severe **behavioural** changes, inc. *hyperactivity*, social *anxiety*; language *delays*, *seizures*

Question 32

Fragile X syndrome in females

Answer 32

Severity *correlated* with degree **X inactivation** (random *silencing* of one copy of X chr in females)

Question 33

FMR1 repeat

Answer 33

***Unstable*** * **No.** repeats can ***expand*** during DNA replication/repair * *Subsequent* generations may have **longer** repeat length * Intermediate → premutation * Premutation → **full** mutation

Question 33

Attention-deficit/hyperactivity disorder (ADHD) Symptoms

Answer 33

**Inattention**, **hyper**activity, **impuls**ivity

Question 34

ADHD inheritance and prevalence

Answer 34

***Multifactorial/polygenic*** disorder * Very common: **~5%** *school*-aged children,~2.5% young adults, ~1% older adults * *Heritability* is **~80%**

Question 35

Genome-wide association studies (GWAS)

Answer 35

Examine **1-10,000,000** common ***SNPs*** distributed along each chromosome * Compare ***allele frequency*** between cases & controls

Question 36

GWAS for ADHD

Answer 36

**27** loci *significantly* associated with disease: * inc. one near ***PTPRF*** (role in **synaptogenesis**) * also associated with **scz**, **ASD**, educational attainment

Question 37

Autism spectrum disorder (ASD) symptoms

Answer 37

**Social** communication/interaction *deficits* & restricted, repetitive, stereotyped **patterns** of behaviors/interests, higher skills in **systemizing**

Question 38

ASD Environmental risk factors

Answer 38

**older** parents, birth **trauma**, gestational **diabetes**, valproate

Question 39

Heritability of ASD

Answer 39

***~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