Kevin Mitchell Rare Disease Day 2016 Presentation

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