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Genetics of Autism
Terms in this set (92)
ASD has a lot of causal....?
There are some points in life where mild autistic traits are....?
Autism and ASD is characterised by broad and narrow definitions - what are the three key aspects of ASD?
1) Social communication deficits - there's a variety of manifestations:
- Gaze issues
- Play issues
- Issues with demonstrating affection
- Issues with demonstrating connection
2) Restrictive repetitive behaviours (which are more disabling):
- Domestic rituals
3) Language deficits (also relates to (1)) - issues with:
- Modulation in social contexts
- Reciprocity (particularly lacking in ASD)
In terms of restrictive repetitive behaviours, people with ASD sometimes get distressed by changes - this can lead to just moderate irritability (comes across as an inflexible person), however on the other end of the spectrum, a child in the absence of routine could have a....?
You can take the three components of ASD and merge them to varying degrees to create something. Coming in the side are the comorbidities - these don't come into the diagnostic criteria, however....?
They come with ASD a lot of the time (e.g. ID, anxiety, ADHD or medical comorbidities like malformations and other somatic diseases)
This is due to the causal heterogeneities of ASD. However remember that comorbidities are not part of the....?
Severe autism (classical autism) is frequently associated with what?
- Intellectual disability
- Medical comorbidities are also frequent
Autism (with a broad diagnostic definition) has a high heritability - about 90% in twin concordance studies (however twin studies are used as an instrument for measuring heritability carries caveats). Modern genome array based estimates say that heritability is likely around....?
Fraternal twins have on average 50% shared genome, and have the same environment - they have less of a purely genetic disorder in terms of concordance, whereas monozygotic twins should be....?
100% (however we have demonstrated 90%??) - rewatch!
So, since there is a heritability of at least 60% that has been shown, ASD is very....?
When you are systemically evaluating a family with a child with ASD, what are the questions that they will ask?
- What caused it?
- Will it happen again?
The key to diagnosis is a recognition that autism....?
a) Carries substantial genetic underpinnings
b) Is causally heterogeneous (so there are challenges for getting across the heterogeneity and looking in the right places)
What are some approaches for the geneticist?
- Empirical recurrence risk (what have people noticed? What has been accounted in families with an individual with ASD? How much recurrence do you get?)
- Pedigree analysis (multi-generation and look at wider family tree)
- Detection of an underlying single gene disorder (through history taking and examination - there are some disorders that present as autism, and if this is the case, there are diagnostic instruments with high precision in place)
- Chromosomal analysis/comparative genomic hybridisation (aka microarray)
- Exome/genome sequencing (this is the expensive big stuff)
Microarray is quite useful - it detects things things that are rare and common in our genomes. As ASD can exhibit multifactorial causation (multiple genetic issues), the things we find in this are useful. Chromosomal analysis is useful in someone with what?
Comorbidities, but less so in someone with classical/severe autism
Recurrence risks are not as neat as a Mendelian disease. There is a recurrence risk of 15-25% for all types of ASD - but there is lower heritability (40%) for what?
Strict autism (ie autism without intellectual disability or comorbidities)
ASD is more commonly diagnosed with time - we don't know whether this is because we are getting a better idea of what it is, finding it with more ease, or perhaps our diagnostic tools are sharpening. However it could also be that there is something out there that is making it....?
More apparent (e.g. as our lives become busier, the differences in ASD become more problematic)
There's a higher risk for those with comorbidities getting ASD. In terms of risk, there's a female : male gender ratio of 1:4 - why are males generating this phenotype more frequently than females?
Research hasn't found anything yet (however there is some indication that males express genes early on that are part of this evolving process)
15-25% recurrence risk is the same kind of recurrence risk as what?
An autosomal recessive condition (so distressing for the families)
The problem with these figures are that....?
- The recurrence risks are high
- We need clear answers to guide reproductive choices
Now we will look at pedigree analysis (which is the next most powerful tool). You can't clinically diagnose autism until what age?
3 years (however there are often concerns before this)
Some people with ASD are doing well at life, and are very interested in certain things (this being the only indication of ASD) - so they have some clear ASD traits but are sometimes hard to....?
Pick up on for a pedigree
Autism appears to be an autosomal dominant disorder causing sporadic presentation?
Often both parents of a kid with ASD are what?
Over-represented in an interest/job type (e.g. engineering) - so there are clearly some subclinical markers in both parents, and then added together results in ASD in the child)
Now we will look at the next step in systematic evaluation of a family with an autistic child - considering single gene disorders. Monogenic syndromic association explains up to....?
10% of ASD (however this is an unlikely proportion - probably more like 3-4%)
What are two commonly cited examples of monogenic syndromic associations with ASD?
- Fragile X syndrome
- Tuberous sclerosis
(people with fragile X don't necessarily have comorbidities, whilst the ones with TS always do)
Fragile X is the most common condition causing ASD? REWATCH
Fragile X syndrome is X-linked - so males are affected and females can be.....?
Either non-penetrant or exhibit variable expressivity
Fragile X syndrome is caused by what?
A triplet repeat expansion
(this sits in the promoter unlike in Huntington's, and it expands outside the normal range (over 44 repeats - normal range is about 1-44 repeats) at which point it starts to shut off the expression of that gene)
Those who have over 200 repeats don't...?
Express the gene at all (and this particular gene is critical for functions such as gaze, language, connection and cognitive abilities - people with this disease have moderate-severe ID)
What is a characteristic feature of this disease?
Gaze eversion and don't connect easily with others (autism is therefore part of the differential diagnosis)
There is a routine clinical test for Fragile X syndrome. Full expansions result in moderate-severe MR in males - what is MR?
With Fragile X syndrome there are some....?
ASD like behaviours noted
Tuberous sclerosis has what inheritance pattern?
TS presents with physical manifestations - so key for diagnosis is clinical examination. What happens in this disease?
Intracerebral space occupying lesions called tubers develop (these are white matter lesions and cause any amount of trouble from ID to seizure, or other neurological dysfunction)
This is an overgrowth type condition, which leads to neurological manifestations. There are also other manifestations where?
(so screen individuals with scans and clinical examinations to see what other organ systems are affected)
So, there is very variable neurological presentation - however this can be readily diagnosed by an experienced practitioner. What is reasonably common due to TS (because it represents a neuro anomaly)?
Traits which occur in tuberous sclerosis can lead to are seen here - this is because this gene is....?
Expressed widely throughout the body and can lead to overgrowth of many different tissues (and so has different pathological manifestations)
Clinical evaluation shows what?
- Fungal infections that appear as patches on skin that are easily to see under UV light
- Spots on teeth
- Acne-like manifestations
Clinical diagnostic criteria for tuberous sclerosis:
There are two loci for tuberous sclerosis - both are genes involved in the....?
Regulation of tissue growth
Loss of both alleles at either loci results in the myriad manifestations of this condition. Recurrences are more or less....?
Avoidable if you are onto the diagnosis
As a somatic event that occurs during the growth of the body, the other allele does what? Something about shutting down both genes???? REWATCH
In terms of genetic analysis of TS, both genes are large genes - and the many variants are detected by sequencing. We look for mutations that are either....?
- De novo
- Inherited (from penetrant or non-penetrant relatives)
Note that you need to consider all loci and all forms of mutations:
- Deletions, whole gene, intragenic
- Point mutations
When we did gene by gene analysis, this was a significant cost. Now what we do is use....?
Gene panels that sequence all the genes in parallel (highly parallel sequencing, with comprehensive analysis in both genes) - which is quite quick and cheap
We don't sequence too much bigger, as otherwise we find things that we don't want to find. So, we just do a panel of genes, and check the genes that could be related - you can order these tests and the company will send you back an....?
Analysis of the genes that you're interested in
However the key principle here is to beware of what?
Exclusionary thinking - a negative genetic sequencing test (can't find the mutation in the two genes) is very often not exclusionary
(this is because you can get mutations in introns and other parts of the genes which you have chosen not to examine because we don't know how to interpret variations here)
Now we will move onto the 4th part of systematically evaluating a family with an autistic child - which is what?
Chromosomal analysis/comparative genomic hybridisation (aka microarray)
Comparative genomic hybridisation uses genomic DNA and looks for a balance in the genome of a test case (e.g. a patient) and a control gene. There is no need for....?
There is differential labelling of patient (red) and normal (green) DNA - and then there is hybridisation of a 1:1 mixture to a spotted DNA array (array-CGH). You then detect relative difference in DNA content of the test vs the normal by differences in....?
Red:green fluorescence ratio
(so you basically anneal one genome with a reference genome - you re-anneal them - and then spread them out, which allows you to see if there is a balance in the genome)
Normally the two genes cancel each other out (yellow) - however if there is more or less of some DNA, this then shows up as....?
Red (duplication) or green (deletion)
So, this allows you to see what is balanced across the genome and what isn't - you then go back to what to check about the balance you are seeing?
Here we can see an example of a deletion at the tip of chromosome 1 that is detected by array CGH - you can see the departure from....?
What can be found using such microarrays?
- Large chromosomal anomalies
- Deletions (of imprinted and non-imprinted loci)
- Chromosomal microdeletions and duplications
Large chromosomal abnormalities that are detectable on karyotype are....?
"private" chromosomal syndromes
Chromosomal anomalies are frequently private, and produce unique patterns of anomalies. Neurological sequelae are almost inevitable and what is common amongst these?
Large chromosomal anomalies account for 1-2% of autism, and other medical morbidities are common. Occasionally these are recurrent, such as what?
Maternally derived duplications of 15q11-13
So, this is the specific one that always comes up in children with autism - the reason this is maternally derived is due to...?
Imprinting (you can't get it from your dad)
This is the reason why you get some genes from one gendered parent. It's important to get an intact maternal copy of chromosome 15 - and in other areas it's more important to get.....?
An intact paternal copy (and the other copy doesn't actually matter)
Those with a pure single chromosomal abnormality account for....?
1-2% of people with autism
Here we can see the chr15q11-13 duplication - the lump seen is a departure from normality (due to duplication). These are maternally derived (the duplicated genes), and as a result you will have a higher risk of....?
An autistic phenotype
15q11-q13 are imprinted loci. The function of imprinted genes differs between the maternal and paternally derived alleles. This is due to what?
Parent specific methylation (and therefore silencing of critical genes) - and 15q11-13 contains such critical genes
Maternal derivation of duplication leads to autism - but we don't know....?
Which genes are important and which aren't
In terms of small chromosomal anomalies and the power of CGH, CGH brings huge resolving power to cytogenic analysis. It detects what?
- "Normal" and "abnormal" imbalance
- "Common" and "rare" anomalies
- De novo and inherited anomalies
- Duplications and deletions
If we look at chromsomal anomalies in ASD, deletions are duplications are found with increased frequency - individuals with ASD are more likely to have....?
Multiple and larger rearrangements
Is there some background wash of chromosomal abnormalities, which although they don't look the same, are more commonly found in autism kids than controls?
The answer is yes
This becomes difficult diagnostically - how can we measure this in the clinical, and conclude whether a deletion or duplication is enough or not enough to determine whether....?
You have ASD (how do we also measure the same threshold in future siblings etc)
At a population level, there's a genetic signal that we can molecularly define, but we can't use this on a single individual in the clinic.
If a kid has ID, don't do chromosomal microarray???? REWATCH
Very often CNVs with causal relevance can be inherited from....?
Health (ie non-penetrant) parents
Some are variable in their expression - e.g. 16p12.2 deletion/duplication which is.....?
"Frequent" - associated with 0.6% of ASD cases
This CNV also causes what?
- Developmental delay +/- obesity
- Non-ASD psychiatric disorders, "normality"
Which are more penetrant, the duplications or deletions?
So, children with this 16p12.2. deletion/duplication have a smaller brain and have ID but not autism???? REWATCH
There are lots of what that are strongly associated with ASD?
CNVs (deletions and duplications)
The take-home message about chromosomal analysis in the CGH era is that there are small imbalances in kids with autism. It's difficult to differentiate between this and....?
Background CNVs in the healthy (which are genuinely benign)
There is also sometimes what for potentially pathogenic CNVs?
A single unitary anomaly is seldom the cause. The concept of what helps?
"Mutational load" - there are many independent genetic factors that must be co-inherited before the ASD phenotype manifests (so these individuals with ASD have crossed some kind of threshold and have their own rare combination of genetic hits which has led to them having developed this)
Now we will move onto looking at exome/genome sequencing - however note that this doesn't lay out the whole genome after all, and you can't....?
Put your finger on all the variation and figure out what this means
Anomalies in some chromosomal regions are identified recurrently and are risk-associated. You can track mutations in what in a few families?
In single genes
Now whole exome/whole genome sequencing studies are identifying what?
An excess of nonsense mutations in genes in cases vs controls (2-4x more)
So, we are finding deleterious changes across the genome in an increased burden in people with autism compared with those that don't - these are non-sense variants within genes that we know will....?
Destroy the function of that allele
What kind of genes are getting hit with recurrency?
There's such a large number of them, that we can't put them on a panel and very easily screen for them all
The most rigorous critiera: de novo, non-synonymous changes in genes predicted to what are most likely to be the most significant?
Alter protein function
However what genes?
The ones we are seeing are likely to the tip of the iceberg - however they tend to be genes involved in synaptic function and chromatin remodelling
They confer independent risk for the development of ASD. There are further studies of this kind underway. Rare variants confer what?
Significant personal liability, but are not common enough to explain most of the heritability
Genes interact with each other in functional groups - there are clouds of genes that are affected in children with autism (e.g. Wnt signalling chromatin remodelling and synaptic function tend to be impaired in children with autism). Children with autism normally have....?
Bigger brains and larger head sizes (what underlies this is possibly an inability to remodel and establish synapses - these children probably have more persisting connections between neurons that haven't been pruned throughout childhood)
One study that did exome sequencing in Autism found what in summary?
That there is:
- Locus heterogeneity
- Mutational heterogeneity
- Oligogenic inheritance (multiple genes that are involved in any one disorder)
There is co-inheritance of all the maternal and paternal mutations, and then there's your own de novo mutations - and this mutational burden gathers and causes autism. However we can't provide....?
Individualised tests for families to predict things though (this is a diagnostic challenge)
Autism is a disease characterised by a strong genetic basis and common inherited factors account for most of this libility. A minority of patients with ASD have an....?
identiable genetic factor or major effect
40% are unaccounted for, 50% have common variation and a smaller % are the ones we have talked about today:
So working up autism involves clinical assessment and what for those with ID?
Positive findings will be significant but it's completely unclear what their positive predictive value will be. Often families are asking for a test with high positive predictive value - such as what?
The heterogeneity and complex architecture of ASD however may preclude this even in the future when technology is optimised. So, we can't be prognostically accurate with this condition, and some tools shouldn't be used for everyone, because our ability to interpret can be...?
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