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Are common
disorders really
collections of rare
disorders?
Kevin Mitchell
Institute of Genetics
Trinity College Dublin
Common vs Rare
Autism
Epilepsy
Schizophrenia
IntellectualDisability
VCFS (22q11)
Fragile XRett
Pitt-Hopkins
TimothyWilliams
Tuberous sclerosis
Angelman
Prader-Willi
Diagnoses of exclusion
• Major diagnostic categories are based on
similarity of symptoms and ignorance of
causes
• Psychological symptoms are defined by
interview/behavioural reports – no blood
tests, brain scans, or other biomarkers
• Underlying mechanisms may be highly
diverse
Genetics reveals diversity of causes
• Traditional cytogenetics
• Molecular technologies to detect
chromosomal deletions and duplications
• Genome sequencing to detect single
mutations
More and more cases of “common disorders”
recognised as discrete, rare genetic conditions
Traditional cytogenetics
Can reveal large differences
Comparative genomic hybridisation
CGH allows detection of even small events
and gives precise molecular information
Can identify which genes disrupted
Whole-genome sequencing
…CCTAAACTTTG…
Genetic variation
• Each of us carries ~150 mutations affecting
different proteins
• Sometimes one or more of those mutations
cause disease
How many cases can be diagnosed?
(2011)
Complexity of genetic effects
• Some cases may have one identifiable genetic cause
• Many others may involve multiple genetic effects
- probably a unique spectrum in each person
• Specific mutations can have diverse effects across
people
Why make genetic diagnoses?
• Diagnostic certainty
• Information on whether mutations are inherited or new
• Prediction of risk to subsequent children
• Therapeutic implications in some cases
• Driving rare disease research
Conclusions
• Common diagnostic categories hide underlying
genetic diversity of causes
• Rare disorders may be collectively much more
common than currently recognised
• Genetics is revealing many underlying causes
• Genetics services need to keep pace with rapid
advances in science
