Trigger 9: Deciphering Developmental Disorder study

Question 1

objective of DDD study

Answer 1

understand the genetics architecture of DD

• catalyse improvement in diagnosis

Question 2

DDD study is a

Answer 2

UK-wide collaborative study with DD families, NHS and the sanger institute

Question 3

DDD strategy

Answer 3

• Systematic clinical phenotyping
• Exome sequencing and microarrays
• Feedback
• Likely genetic diagnoses
• Share data widely

Question 4

how many families involved

Answer 4

13,500

Question 5

clinical data taken

Answer 5

age, sex, family history, quantitative data (weight/height etc) and phenotypes

Question 6

what are used to find CNVs

Answer 6

microarrays of the proband

Question 7

proband

Answer 7

a person servicing a the starting point of the genetic study of a family

Question 8

which microarray is used

Answer 8

2m-prbe array CGH

Question 9

exome sequencing used to detect

Answer 9

SNVs/ indwells - all of axons plus some regulatory regions

Question 10

the study diversity if representative of the UK clinical population

Answer 10

• mostly 0-16
• diverse ancestry, 5% consanguinity
• severe undiagnosed DD
• wide range of phenotypes

Question 11

before the study many participants were

Answer 11

undiagnosed

Question 12

what had most participants had before the study

Answer 12

clinical microarray 1+ targeted genetic test (55%)

Question 13

why is family trip exome sequencing useful for diagnosing DDs

Answer 13

• Exclusion of benign inherited variants
• Finding de novo variants
• Determining if recessive variants in child are inherited from carrier parents
• Finding new disease genes

Question 14

trio analysis

Answer 14

exome sequencing of an affected probing and their unaffected parents

Question 15

trio analysis is

Answer 15

expensive £1760-2200 (dependent on whether the whole genome or just rare disease genome is sequenced

Question 16

important issues for discussion during consent process

Answer 16

• 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

Question 17

genetic data from child and both parents hugely reduces

Answer 17

the number of candidate causal variants

Question 18

two approaches to variant analysis

Answer 18

translation and research

Question 19

translation- approach to variant analysis

Answer 19

-conservative approach - likely pathogenic variants in published DD genes

Question 20

translation approach involves

Answer 20

reporting to clinician for evaluation

Question 21

translation results are

Answer 21

shared publicly via DECIPHER database

Question 22

Research- approach to variant analysis

Answer 22

• statistical approach (rigorous) - new genes, complex variants and novel analysis

Question 23

if both parents have healthy allele but child has mutation..

Answer 23

due to de novo dominant mutation

Question 24

if both parents have healthy allele but child has mutation, what is the risk of their second child having the mutation

Answer 24

<1%

Question 25

if both parents are N/n, what is the risk of inheriting the disease

Answer 25

75% - draw out

Question 26

if both parents are N/n, , what the risk of inheriting in an autosomal dominant fashion (Nn)

Answer 26

50%

Question 27

if both parents are N/n, , what s the risk of inheriting the disease in an autosomal recessive manor

Answer 27

25%

Question 28

if the disease is X-linked and the mother is N/n what is the likelihood of the son getting the disease allele

Answer 28

50%

Question 29

how can we prove that a novel variant i a previously uncharacterised gene causes a monogenic disease like DD

Answer 29

1. 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

Question 30

enrichment analysis

Answer 30

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.

Question 31

there are statistical tests of enrichment for

Answer 31

damaging de novo mutations for every gene in the genome

Question 32

how does enrichment analysis work

Answer 32

The method uses statistical approaches to identify significantly enriched or depleted groups of genes

Question 33

enrichment analysis graph

Answer 33

statistical test of enrichment of damaging de novo mutations for every gene in the genome

Question 34

sequence mutations increase with

Answer 34

paternal and maternal age

Question 35

parental age effect is mostly due to

Answer 35

replication errors in mitosis

Question 36

mutations caused by parent age are mostly due to

Answer 36

replication errors in mitosis

Question 37

paternal age effect

Answer 37

single gene defects e.g. can relate to birthweight, congenital disorders, life expectancy, and psychological outcomes

Question 38

maternal age effect causes

Answer 38

structural mutations - mostly due to recombination errors in meiosis I - evidenced by obsereved trisomies

Question 39

diagnostic yield of the DDD study

Answer 39

around 40% - mostly (70%) de novo mutations - mostly thanks to new gene discovery

Question 40

Coffin-Siris syndrome caused by

Answer 40

caused by de novo loss of function mutations ARID1B

Question 41

ARID1b

Answer 41

is a chromatin remodeller (changes DNA accessibility for gene expression)

Question 42

phenotypic spectrum of Coffin-Siris (ARID1b)

Answer 42

Developmental delay, speech delay, abnormalities in pinky finger or toes, short sighted, feeding difficulties Overlaps with other disorders

Question 43

treatment for Coffin-Siris (ARID1b) syndrome

Answer 43

no treatment- parents can be genetically counselled on the recurrence risk

Question 44

how can more DD be found

Answer 44

To find more DD genes- we need more samples… Options: 1. Recruit more patients (not possible with DDD!) 2. Persuade other researchers to give us their data (i.e. collaborate with other similar cohorts) 3. Share our data with other researches - openly or managed access - ethical framework required

Question 45

why can it often be challenging to find a diagnosis?

Answer 45

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