Genomic medicine

Question 1

Situations in which genomic medicine is useful?

Answer 1

• Diagnosis
• Identifying people at increased risk
• Tracking epidemics
• Personalising drug treatments (including cancer)
• Developing new therapies

Question 2

Three types of gene mutation?

Answer 2

1) Inherited – autosomal/ X-linked recessive/dominant
2) De novo dominant mutation
3) Mosaic mutation

Question 3

What is a mosaic mutation or mosaicism?

Answer 3

Two or more populations of cells with different genotypes in one individual

Question 4

Limits to sequencing by synthesis?

Answer 4

• Poor at capturing simple repeats, and GC rich areas
• Misses promoters, UTRs, microRNAs
• Targeted panels may be better

Question 5

Main principle behind sequencing by synthesis?

Answer 5

Recordign energy given off by marked base pairing

Question 6

Are mixed race families more or less likely to have the same recessive allele?

Answer 6

Less likely

Question 7

What is a germline mutation and a somatic mutation?

Answer 7

Germline: is a mutation in an egg or sperm cell itself

Non-germ-line tissue mutation, so can’t be inherited

Question 8

Are many inherited cancers due to oncogenes or tumour suppressant gene mutations?

Answer 8

tumour suppressant

Question 9

What are DNA repair genes, what could their mutation lead to?

Answer 9

Genes responsible for correcting the mutations in DNA, a mutation in a DNA repair gene can lead to cancer through the propagation of mutated onco/tunour suppressant gene.

Question 10

Why can next-gen sequencing be difficult in cancers?

Answer 10

• Cancer genomes are complex and diverse
• Most cancers are aneuploid (abnormal chromosome number)
• Limited biopsy DNA
• Whole genome amplification might be needed to identify certain mutations (e.g. fusions)
• Often has necrotic, apoptotic cells in sample
• Formalin can damage DNA
• Tumours can contain normal DNA, tumour DNA, and different tumour clones

Question 11

What are driver and passenger gene mutations?

Answer 11

Drivers give the clone a selective advantage and contribute to oncogenesis

Passengers have no effect on clone survival

Question 12

Why would next-gen sequencing be useful in cancer?

Answer 12

Identify the exact gene mutations causing the cancer

Question 13

What is minimal residual disease and how is this useful in cancer?

Answer 13

measures the proportion of tumour cells with a defining mutation

e.g. If the ratio of allele A:allele B is no longer 50:50 then this suggests a loss of heterozygosity, therefore clonal expansion, therefore cancer

Question 14

Use of minimal residual disease testing in cancer?

Answer 14

• Prognosis
• Quantifying drug response
• Monitoring remission and relapse
• Guiding treatment

Question 15

What is SCID?

Answer 15

Severe combined immunodeficiency

Question 16

What are PIDs?

Answer 16

Primary immune deficiency

Question 17

Some treatments for PIDs?

Answer 17

Folinic acid

bone marrow transplant

Question 18

Types of next generation sequencing (NGS)?

Answer 18

Whole genome sequencing

Whole exome sequencing

Targeted gene panels

Question 19

What percentage of disease causing variants are in the exome?

Answer 19

85%

Question 20

What are SNIPS?

Answer 20

Single nucleotide polymorphisms

Heterozygous - different

Question 21

How much roughly would it cost to have your genome sequenced now?

Answer 21

About £1000

Question 22

Problems when not doing whole genome sequencing?

Answer 22

Simple repeats are poorly captured

Whole exome is not the WHOLE exome - some will be missing

Clinical exome evolves over time

Question 23

Best choice in individuals to sequence if a child has a genetic disease to find the cause?

Answer 23

Either closely related and unaffected individuals

Or distantly related affected individuals

Question 24

What is tiered analyses?

Answer 24

When you have a patient with a specific condition and you first look at the genes we know are involved in that condition

Question 25

How can you filter data?

Answer 25

Tiered analysis

Mode of inheritance e.g. it’s X linked so look at things only on X

Synonymous variants - codes for the same amino acid

Look specifically at things we know make a big difference e.g. like Frameshifts, stop codon.

Concordant variants - if the mutation is seen in unaffected individuals it can be discarded

Conservation metrics - whether it has been the same in evolution

Question 26

What is the genomics england programme?

Answer 26

Sequence rare disease and cancer patients

Put it behind a safe firewall

Allow access from selected individuals who can then feed back into treatment/drug design

Question 27

What is JMML what mutations are associated with it?

Answer 27

Germline CBL mutations