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 >20,000 genes 3,000,000,000 base pairs of DNA X 2 6,000,000,000 base pairs of DNA 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 Autosomal dominant disease = one mutation, one wrong base pair in 6 billion Autosomal recessive disease = two mutations, two wrong base pairs in 6 billion All you have to do is find one or two wrong bases in 6,000,000,000 One or two typos in 50 years of typing
Dominant disease Mut/N N/N Mut/N N/N N/N N/N Mut/N N/N N/N Mut/N N/N Mut/N • Half of the children of an affected parent are affected • Huntington’s disease
Recessive disease N/N mut/N N/N mut/N mut/N N/N mut/N mut/N mut/N N/N N/N mut/N mut/N mut/mut • 1:4 children affected. Cystic fibrosis. Frequently, as in this family, there may be consanguinity
X-linked recessive disease N mut/N N N mut/N mut N/N N mut/N • Affects mostly boys, while girls/women are mostly carriers. • Duchenne muscular dystrophy
Isolated cases
De novo mutation Father Mother Affected child ACTA1 Exon 5: c.808G>T (p.Gly270Cys)
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
Gene discovery – foetal akinesia Family 1 Family 2 Turkey Western Australia 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
Next generation sequencing diagnostics 2018 • 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.
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 do n’ 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 Carrier mum • Affects mostly boys, while girls/women are mostly carriers.
X-linked: Duchenne Muscular Dystrophy Affected son Unaffected Control Mother Courtesy of Padma Sivadorai, PathWest
Recessive disease mut/N mut/N N/N mut/N mut/N mut/mut • 1:4 children affected • Cystic fibrosis – 1:24 Europeans • Spinal muscular atrophy: 1:40-50 - any ethnicity
Autosomal Recessive Disease Unaffected Control Affected child Father Mother Courtesy of Padma Sivadorai, PathWest
Duchenne muscular dystrophy: X-linked recessive Carrier mum • Affects mostly boys, while girls/women are mostly carriers.
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 • Historical and current preconception carrier screening programs • Carrier detection programs for recessive diseases: o Tay-Sachs and other diseases in the Ashkenazi population o 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%
Israeli Carier Screening Program Genet Med 18 , 203-206 (2016) 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.
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 Genet Med. 2016 Sep 22. doi: 10.1038/gim.2016.143. Analysed >450 rare diseases: • 2% of the Western Australian population • 9.9% of hospital discharges • 10.5% of hospital inpatient costs = $395m a year
Politics
1 st 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 8 th 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?
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