9 - diagnosing developmental disorders

Question 1

NGS

Answer 1

next generation sequencing

parallel sequencing of short fragments of DNA

high throughput –> can sequence whole genomes (GWAS)

Question 2

importance of genome-wide sequencing

Answer 2

enables discovery of novel disease-causing variation in previously unclassified genes

Question 3

targeted next gen sequencing

Answer 3

sequence panel of genes where you think the disease causing variant is

Question 4

what was the UK-wide collaberative study

Answer 4

combined families with NHS and Sanger institute

aimed to understand what genes/variants cause developmental diseases to improve diagnosis

Question 5

method of UK-wide collaberative study

Answer 5

recruited 13,500 families (trios)

DNA sent to sanger for systematic clinical phenotyping

• -> exome sequencing (of parents and child to look for SNVs)
• -> microarrays (to look in probands for CNVs)

family and NHS given information about diagnosis

Question 6

reason behind trio sequencing approach

Answer 6

mum, dad and child all sequenced

reduces the number of candidate causal variants (narrows down diagnosis)

(think venn diagram –> child is overlap from mother and father)

allows identification of the 70-120 de novo variants

Question 7

diagnostic yield of UK-wide collab study

Answer 7

intially 27% - 2014

curently 40% - 2018

Question 8

coffin-siris ARID1B syndrome

Answer 8

genetic developmental disorder
characterised by hypoplasia of 5th digit, coarse facial features and intellectual delay
–> broad phenotype

rare
no current treatment

Question 9

how do we prove that novel variants are disease causing

Answer 9

find similar patients with similar variants in the same (previously uncharacterised) genes

show unnaffected individuals do not carry similar variants in the same gene

made easier by sharing of databases

Question 10

animal model to show functional effects of variants

Answer 10

zebrafish

mimic effect of mutation and see what effect it has on the protein

Question 11

use of statistical methods to show variants in disease cohort

Answer 11

calculate likelihood that observed outcome will equal what is expected

chance that you see mutation without disease caused

Question 12

parental age effect

Answer 12

number of de novo mutations in sperm increases with parental age

prevalence of dominant DD increases to 1 in 300

Question 13

challenges of working with genome-wide sequencing data

Answer 13

you dont know family history of disease
people carry disease-causing variants without having disease
difficult to predict severity
ethical issues

Question 14

ethical issues associated with genome-wide seqencing studies

Answer 14

1 - data sharing

2 - might find out things you weren’t looking for
e.g. finding gene for huntingtons disease (patient doesnt know they will develop it)