genes? Professor Nigel Laing AO, FAHMS, FFScRCPA, FHGSA - - PowerPoint PPT Presentation

Genetics: what do you have hidden in your genes?

Professor Nigel Laing AO, FAHMS, FFScRCPA, FHGSA

Neurogenetic Diseases Group, Harry Perkins Institute of Medical Research and Centre for Medical Research University of Western Australia and Neurogenetics Unit, Department of Diagnostic Genomics, PathWest, Department of Health, Western Australia. Email – nigel.laing@perkins.uwa.edu.au

We are all different

One of the reasons we are different is genetics

Our genetic material is DNA (Deoxyribonucleic acid)

• In the nuclei of all our cells
• Except red blood cells – which don’t

have nuclei

Human genome

3,000,000,000 base pairs of DNA X 2 Autosomal dominant disease = one mutation, one wrong base pair in 6 billion All you have to do is find one or two wrong bases in 6,000,000,000 6,000,000,000 base pairs of DNA Autosomal recessive disease = two mutations, two wrong base pairs in 6 billion

It would take a typist typing 8 hours a day half a century to type the genome

http://www.thehumangenome.co.uk/THE_HUMAN_GENOME/Primer.html

One or two typos in 50 years of typing >20,000 genes

Dominant disease

Mut/N Mut/N Mut/N N/N N/N N/N N/N N/N Mut/N N/N Mut/N N/N

• Half of the children of an affected parent are affected
• Huntington’s disease

Recessive disease

N/N mut/N mut/N mut/N mut/N N/N N/N N/N mut/N mut/N mut/N mut/N N/N mut/mut

• 1:4 children affected. Cystic fibrosis. Frequently, as in this family, there may be consanguinity

X-linked recessive disease

• Affects mostly boys, while girls/women are mostly carriers.
• Duchenne muscular dystrophy

mut/N mut/N mut/N N N N N N/N mut

Isolated cases

De novo mutation

ACTA1 Exon 5: c.808G>T (p.Gly270Cys) Affected child Mother Father

Disease gene discovery

Next generation sequencing (NGS) disease gene discovery

Exome sequencing – sequencing all >20,000 genes in a person at once

Foetal Akinesia

Dr Gina Ravenscroft

Western Australia Turkey Family 1 Family 2

Gene discovery – foetal akinesia

Baby died at 5 days of age Babies died at 20 days and at 3 months

Mutations in the same gene KLHL40

• Family 1: two mutations in KLHL40

– c.932G>T, p.Arg311Leu – c.1516A>C, p.Thr506Pro

• Family 2 (consanguineous): two copies of one mutation in KLHL40

– c.1582G>A, p.Glu528Lys

• “Coalition of the willing”: Perth, Helsinki, Tokyo/Yokohama and Boston
• Sequenced KLHL40 in 143 foetal akinesia cases
• 19 mutations in 28 families

KLHL40 FADS-NEM

Research & Diagnosis

• In 2018, molecular diagnostics provides accurate diagnosis faster to

many more patients than previously possible

• The diagnostic lab in PathWest, QEII is a national referral centre for

Australia and New Zealand for neuromuscular disorders.

• It is therefore providing a diagnostic service to most of 29 million people.

Next generation sequencing diagnostics 2018

Helping couples avoid further affected children

My experience in molecular diagnostics over the last thirty years is: Most couples, if they know they are at risk of passing on a severe genetic condition to their children, will, given the chance, not do so. There are of course couples for whom this does not fit with their values. Through NGS diagnostics we now analyse hundreds of genes for hundreds of genetic disorders. We now help many more couples in known families avoid passing the family genetic condition to their children.

But what about couples that don’t know they are at risk?

We are all at risk from our genetics

The calculation is, that each of us is carrying 3-5 lethal recessive diseases This means that when any of us have children, we play what I have called “genetic roulette”, since most of us have no idea which 3-5 lethal or other recessive genetic diseases we are carrying.

TEDxUWA – Genetic Roulette

TEDxUWA “Playing genetic roulette” https://www.youtube.com/watch?v=ZkOLTfEyLXg

Duchenne muscular dystrophy: X-linked recessive

• Affects mostly boys, while girls/women are mostly carriers.

Carrier mum

X-linked: Duchenne Muscular Dystrophy

Affected son Mother Unaffected Control

Courtesy of Padma Sivadorai, PathWest

Recessive disease

mut/N mut/N mut/N mut/N N/N mut/mut

• 1:4 children affected
• Cystic fibrosis – 1:24 Europeans
• Spinal muscular atrophy: 1:40-50 - any ethnicity

Autosomal Recessive Disease

Mother Unaffected Control Affected child Father

Courtesy of Padma Sivadorai, PathWest

Duchenne muscular dystrophy: X-linked recessive

• Affects mostly boys, while girls/women are mostly carriers.

Carrier mum

Finding carriers rather than diagnosing affected children

• “Our goal is to shift ascertainment to carrier females rather than

ascertainment by the birth of an affected male.”

– Roses, A. D. Archives of Neurology 45(1): 84-85 (1988).

Finding carriers before they have affected children = preconception carrier screening

Preconception carrier screening (PCS) allows couples the possibility of avoiding having children with severe genetic conditions.

Preconception carrier screening

• Carrier detection programs for recessive diseases:
• Tay-Sachs and other diseases in the Ashkenazi population
• Thalassemia in Mediterranean countries

➢ massively decreased the incidence of the diseases. ➢ After 10 years of the Ashkenazi Tay-Sachs program, the incidence of Tay Sachs had been reduced by >90%. ➢ Within three years of instigating the thalassaemia prevention programs in Mediterranean countries the birth rate of thalassaemia had been reduced by 50-80%

• Historical and current preconception carrier screening programs

Israeli Carier Screening Program

Now screening >60,000 individuals a year for multiple recessive diseases Reproductive options for couples determined to be at risk, such as preimplantation genetic diagnosis, are part of the program and free of charge. Genet Med 18, 203-206 (2016)

Preconception carrier screening in Australia

• In Victoria (Melbourne), preconception carrier screening for spinal muscular

atrophy, cystic fibrosis and Fragile X has been offered since 2012 on a user pays basis. >12,000 individuals have been screened.

• Screening has been in place in the Jewish population in New South Wales

and Victoria for over 20 years.

• In the 20 years of this program, no child with Tay-Sachs disease has

been born to a screened couple, but children with Tay-Sachs are born to unscreened non-Jewish couples in Australia.

• Almost no preconception carrier screening in other States
• Various commercial companies offer preconception carrier screening

frequently direct to the consumer.

International opinion is evolving

American College of Obstetricians and Gynecologists “Opinion“ March 2017 (Obstetrics & Gynecology 129: (3) e35)

“Each obstetrician–gynecologist or other health care provider or practice should establish a standard approach that is consistently offered to and discussed with each patient, ideally before pregnancy.”

What will decide whether Australia has population- wide preconception carrier screening?

• Economics:
• Every new health initiative has to be cost effective
• Paradoxically, governments and government economists (like my

son) will be more interested in preconception carrier screening if expensive therapies are instituted, since those therapies will make genetic disease more expensive.

• Politics:
• If populations want preconception carrier screening, it will come.
• Population-wide preconception carrier screening has been

advocated for by disease associations like the Spinal Muscular Atrophy Society of Australia for a number of years and has been raised in Federal Senate

Economics

Reducing the burden of genetic disease

Around 50% of mortality prior to age one in Western Australia is caused by “rare diseases” many of which are genetic.

Health econmomic impact of genetic disease

Analysed >450 rare diseases:

• 2% of the Western Australian population
• 9.9% of hospital discharges
• 10.5% of hospital inpatient costs = $395m a year

Genet Med. 2016 Sep 22. doi: 10.1038/gim.2016.143.

Politics

1st March 2018 “Mackenzie’s mission”

Health Minister Greg Hunt “would like to see pre-conception testing become routine for everyone thinking about starting a family”.

Federal Health Minister Hunt’s Office – budget day 8th May 2018

“Mackenzie’s mission”: $20m for a preconception carrier screening trial

Genetic diseases & Insurance

What is the role of insurance in genetic disease? Genetic disease status not allowed to be taken into account in health insurance in Australia? Moratorium in place on using genetic information in relation to life insurance in Australia?

Summary

• Most of us don’t know what we have hidden in our genes.
• Preconception carrier screening has the potential to prevent a large

proportion of infant mortality and morbidity and cost to society.

• It has long been my opinion that preconception carrier screening

should be a choice available to the community as a whole.

• Australia has a lot of catching up to do in this area.
• Federal Health Minister Greg Hunt announced on 1st March 2018

that he wanted carrier screening available free to all Australians within 10 years.

• In the Federal Budget on 8th May Minister Hunt announced the

$20m Mackenzie’s Mission as the first step to seeing this happen.

Acknowledgements

University of Western Australia, Harry Perkins Institute of Medical Research: Dr Gina Ravenscroft, Dr Rhonda Taylor, Josh Clayton, Elyshia McNamara, Royston Ong, Sarah Beecroft, Hayley Goullee, Adriana Messineo, Chris Wallis, Sam Edwards, Mandi Macshane, Tina Ly, Western Australian Department of Health, PathWest, Diagnostic Neurogenetic Unit: Dr Mark Davis, Dr Cheryl Wise, Dr Rebecca Gooding, Dr Fathin Faiz, Dr Desiree Ho, Dr Michael Fietz, Padma Sivadorai, Dan Trajanoski, Western Australian Department of Health, Neurogenetic Unit Clinical Professor Phillipa Lamont Western Australian Department of Health, Office of Population Health Genomics Dr Kristen Nowak Funding: Australian National Health and Medical Research Council (NHMRC) US Muscular Dystrophy Association Association Francaise contre les Myopathies Perpetual Trustees Helen Leach Foundation

Questions?