Genomics

Question 1

How many genes in genome

Answer 1

500,000

Question 2

How many base pairs in genome

Answer 2

3-4 billion

Question 3

How much variation in genome

Answer 3

4-5million

Question 4

Phenotype examples of DD

Answer 4

Intellectual disability/developmental delay (87%)
ASD (10%)
Seizures (24%)
Polydactyly (1%)

Question 5

How many genes associated with DD

Answer 5

more than 1500

Question 6

Intronic/intergenic

Answer 6

Between genes/exons

Don’t directly affect protein produced (more likely transcription or splicing)

Question 7

Gene/coding/exonic

Answer 7

Silent (synonymous)
Missense (non-synonymous)
Nonsense (premature STOP) (cause nonsense mediated decay)
Framwshift

Question 8

Multi exon/multigene

Answer 8

Structural
Affect multiple genes
e.g. CNV

Question 9

Molecular genetics

Answer 9

Sequence specific genes or genotyping specific small mutations (based on phenotype)

Question 10

Cytogenetics

Answer 10

Looking at large structural changes across genome to explain phenotype

Question 11

Sanger Sequencing

Answer 11

Stops at different amino acids, letting off light

Question 12

NGS

Answer 12

Illumina 450K

Massively parallel, fast, cheap

Question 13

Targeted NGS

Answer 13

Gene panels based on phenotype

Question 14

WGS or WES with NGS

Answer 14

clinical exome = 4000 variants - doesn’t allow for gene discovery

Question 15

How to identify which is the disease causing variant?

Answer 15

Find other patients with similar phenotypes with similar variants in same gene
Show unaffected individuals don’t carry similar variants
Tes segregation in family members and other affected families
Use functional studies to match variant effect and phenotype
Statistical models to show enrichment in disease cohort

Question 16

Challenges of GWS data

Answer 16

Time consuming (lots of it)
Requires good, standardised phenotyping from clinician
Too much data (most variation is benign)
Disease mechanism/inheritance may be unknown
Phenotypes have multiple genetic causes

Question 17

DD key mutations

Answer 17

ARID1B
ATRX
CUL4B
MECP2

Question 18

Impact of correct molecular diagnosis

Answer 18

Highlight need for further diagnostic investigations
Facilitatae appropriate access to healthcare resources
Reduce pronostic uncertainty
Provide guidance on risk counselling (family planning)
Can help understand disease pathways and develop treatments

Question 19

Bardet-Biedl syndrome

Answer 19

SNVs/INDELs in 1 of 20 genes

Autosomal recessive

Question 20

KTM2B

Answer 20

Histone lysine methylation by mixed lineage lukemia proteins
Progressive childhood onset dystonia (neurological movement disorder)
Marked clinical benefit with deep brain stimulation - restored ambulation in some cases

Question 21

16p11.2 microdeletion/duplication

Answer 21

CNV, de novo dominant mutations
Causes diability, autism, developmental delay
Duplication = underweight
Deletion = obesity

Question 22

16p11.2 microdeletion/duplication

Answer 22

CNV, de novo dominant mutations
Causes diability, autism, developmental delay
Duplication = underweight
Deletion = obesity

Question 23

Framingham scale

Answer 23

10 year risk score for fatal CV events
BP, cholesterol, age, gender, smoking status
Doesn’t include obesity