Genomics Flashcards
How many genes in genome
500,000
How many base pairs in genome
3-4 billion
How much variation in genome
4-5million
Phenotype examples of DD
Intellectual disability/developmental delay (87%)
ASD (10%)
Seizures (24%)
Polydactyly (1%)
How many genes associated with DD
more than 1500
Intronic/intergenic
Between genes/exons
Don’t directly affect protein produced (more likely transcription or splicing)
Gene/coding/exonic
Silent (synonymous)
Missense (non-synonymous)
Nonsense (premature STOP) (cause nonsense mediated decay)
Framwshift
Multi exon/multigene
Structural
Affect multiple genes
e.g. CNV
Molecular genetics
Sequence specific genes or genotyping specific small mutations (based on phenotype)
Cytogenetics
Looking at large structural changes across genome to explain phenotype
Sanger Sequencing
Stops at different amino acids, letting off light
NGS
Illumina 450K
Massively parallel, fast, cheap
Targeted NGS
Gene panels based on phenotype
WGS or WES with NGS
clinical exome = 4000 variants - doesn’t allow for gene discovery
How to identify which is the disease causing variant?
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
Challenges of GWS data
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
DD key mutations
ARID1B
ATRX
CUL4B
MECP2
Impact of correct molecular diagnosis
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
Bardet-Biedl syndrome
SNVs/INDELs in 1 of 20 genes
Autosomal recessive
KTM2B
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
16p11.2 microdeletion/duplication
CNV, de novo dominant mutations
Causes diability, autism, developmental delay
Duplication = underweight
Deletion = obesity
16p11.2 microdeletion/duplication
CNV, de novo dominant mutations
Causes diability, autism, developmental delay
Duplication = underweight
Deletion = obesity
Framingham scale
10 year risk score for fatal CV events
BP, cholesterol, age, gender, smoking status
Doesn’t include obesity
