Trigger 9: Deciphering Developmental Disorder study Flashcards
objective of DDD study
understand the genetics architecture of DD
- catalyse improvement in diagnosis
DDD study is a
UK-wide collaborative study with DD families, NHS and the sanger institute
DDD strategy
- Systematic clinical phenotyping
- Exome sequencing and microarrays
- Feedback
- Likely genetic diagnoses
- Share data widely
how many families involved
13,500
clinical data taken
age, sex, family history, quantitative data (weight/height etc) and phenotypes
what are used to find CNVs
microarrays of the proband
proband
a person servicing a the starting point of the genetic study of a family
which microarray is used
2m-prbe array CGH
exome sequencing used to detect
SNVs/ indwells - all of axons plus some regulatory regions
the study diversity if representative of the UK clinical population
- mostly 0-16
- diverse ancestry, 5% consanguinity
- severe undiagnosed DD
- wide range of phenotypes
before the study many participants were
undiagnosed
what had most participants had before the study
clinical microarray 1+ targeted genetic test (55%)
why is family trip exome sequencing useful for diagnosing DDs
- Exclusion of benign inherited variants
- Finding de novo variants
- Determining if recessive variants in child are inherited from carrier parents
- Finding new disease genes
trio analysis
exome sequencing of an affected probing and their unaffected parents
trio analysis is
expensive £1760-2200 (dependent on whether the whole genome or just rare disease genome is sequenced
important issues for discussion during consent process
- capacity for consent/assent - likelihood of finding a diagnosis - timescale for finding a diagnosis - potential for treatment - implications for other family members - importance of data sharing - potential for incidental findings o parent not related as expected o health related (adult onset, carrier status etc) o policy on feedback
genetic data from child and both parents hugely reduces
the number of candidate causal variants
two approaches to variant analysis
translation and research
translation- approach to variant analysis
-conservative approach - likely pathogenic variants in published DD genes
translation approach involves
reporting to clinician for evaluation
translation results are
shared publicly via DECIPHER database
Research- approach to variant analysis
- statistical approach (rigorous) - new genes, complex variants and novel analysis
if both parents have healthy allele but child has mutation..
due to de novo dominant mutation
if both parents have healthy allele but child has mutation, what is the risk of their second child having the mutation
<1%
if both parents are N/n, what is the risk of inheriting the disease
75% - draw out
if both parents are N/n, , what the risk of inheriting in an autosomal dominant fashion (Nn)
50%
if both parents are N/n, , what s the risk of inheriting the disease in an autosomal recessive manor
25%
if the disease is X-linked and the mother is N/n what is the likelihood of the son getting the disease allele
50%
how can we prove that a novel variant i a previously uncharacterised gene causes a monogenic disease like DD
- Find other similar patients with similar variants in the same gene 2. Show unaffected individuals do not carry similar variants in same gene 3. Test segregation in family members and other affected families 4. Use functional studies to show effect of variant 5. Use statistical methods to show enrichment of variants in disease cohort
enrichment analysis
s a method to identify classes of genes or proteins that are over-represented in a large set of genes or proteins, and may have an association with disease phenotypes.
there are statistical tests of enrichment for
damaging de novo mutations for every gene in the genome
how does enrichment analysis work
The method uses statistical approaches to identify significantly enriched or depleted groups of genes
enrichment analysis graph
statistical test of enrichment of damaging de novo mutations for every gene in the genome
sequence mutations increase with
paternal and maternal age
parental age effect is mostly due to
replication errors in mitosis
mutations caused by parent age are mostly due to
replication errors in mitosis
paternal age effect
single gene defects e.g. can relate to birthweight, congenital disorders, life expectancy, and psychological outcomes
maternal age effect causes
structural mutations
- mostly due to recombination errors in meiosis I
- evidenced by obsereved trisomies
diagnostic yield of the DDD study
around 40%
- mostly (70%) de novo mutations
- mostly thanks to new gene discovery
Coffin-Siris syndrome caused by
caused by de novo loss of function mutations ARID1B
ARID1b
is a chromatin remodeller (changes DNA accessibility for gene expression)
phenotypic spectrum of Coffin-Siris (ARID1b)
Developmental delay, speech delay, abnormalities in pinky finger or toes, short sighted, feeding difficulties
Overlaps with other disorders
treatment for Coffin-Siris (ARID1b) syndrome
no treatment- parents can be genetically counselled on the recurrence risk
how can more DD be found
To find more DD genes- we need more samples…
Options:
- Recruit more patients (not possible with DDD!)
- Persuade other researchers to give us their data (i.e. collaborate with other similar cohorts)
- Share our data with other researches
- openly or managed access
- ethical framework required
why can it often be challenging to find a diagnosis?
Enormous amount of genetic variation
Every genome contains novel variation
Most genetic variation is benign
Phenotypic and genetic heterogeneity
Disease inheritance and mechanism may be unknown
Phenotypes may have more than one genetic cause
