Pre-pregnancy genetic screening

7th Annual Obstetric Malpractice Conference David Amor 22nd June 2015 VCGS is a not for profit subsidiary of Murdoch Childrens Research Institute and the main provider of clinical and pathology genetics services in Victoria

All couples hope for a healthy baby; however human reproduction is hazardous

•  4% of all babies are born with a congenital abnormality or genetic disorder that is evident at birth

•  Most people have at least one recognised genetic disease

•  All people are born with a genetic predisposition to various medical problems

•  Every person’s genome contains 50-100 variants that are expected to cause genetic disease

Wrongful birth litigation may occur following birth of a child with a genetic disorder when

1.  A genetic risk was not identified prior to pregnancy 2.  A genetic disorder was not detected during the pregnancy

Inheritance   Able  to  detect  at  risk  couples  prior  to  pregnancy  

Able  to  detect  during  pregnancy  

Inherited    dominant   +   +  New  dominant   -­‐   +  Autosomal  recessive   +   +  X-­‐linked   +   +  Chromosomal   +/-­‐   +  Polygenic   -­‐   +/-­‐  Epigene@c   -­‐   +/-­‐  

Your  baby  has  been  diagnosed  

with  a  rare  gene@c  disease  

Circa  1998  

Unfortunately  we  do  not  understand  this  fully.    Gene@c  tes@ng  is  not  possible,  and  it  

could  not  have  been  prevented  

Circa  1998  

OK,  thanks.  

Circa  1998  

Testing technologies and practices relatively stable (and limited) from 1998-2013 •  Taking a family history •  Down syndrome screening •  CVS and amniocentesis •  Ultrasound

Allowing various reproductive options to be exercised: •  TOP •  PGD •  Not have children •  Accept risk

Your  baby  has  been  diagnosed  with  rare  gene@c  

disease  

Circa  2015  

We’ve  iden@fied  the  faulty  gene  and  both  of  you  are  carriers  

Circa  2015  

Couldn’t  this  have  been  picked  up  

during  pregnancy?  

Circa  2015  

Nobody  warned  us  this  might  happen.  

Circa  2015  

…and  I  told  our  doctor  we  wanted  ALL  the  tests….  

Circa  2015  

Is  there  someone  we  can  sue?  

Circa  2015  

New genetic technologies are currently transforming reproductive genetics

1. Pre-pregnancy genetic carrier screening using next generation sequencing

(NGS) This technology is transformative because it offers the ability to simultaneously test for large numbers of genes in a cost effective manner. Availability of preimplantation genetic diagnosis (PGD) depends on identification of risk prior to pregnancy

2. Non-invasive prenatal diagnosis (NIPD)

This technology is transformative because it enables examination of fetal DNA without any risk to the fetus

We all carry multiple recessive genes

The ‘long tail’ of recessive genetic disease

0  

0.005  

0.01  

0.015  

0.02  

0.025  

0.03  

0.035  

0.04  

Carrier  frequ

ency  

Disease  frequency  

History of genetic screening in Australia Until now, the single gene conditions for which pre-pregnancy genetic carrier screening is undertaken are: •  Haemoglobinopathies

(thalassaemia)

•  Autosomal recessive diseases more common in the Ashkenazi Jewish community including Tay-Sachs disease

•  Cystic fibrosis

Population carrier screening for CF •  Cystic fibrosis (CF) is the most common inherited life shortening

condition affecting Australian children, with a carrier frequency of 1 in 25.

•  Most children with CF (94%) have no family history of the condition.

•  The Human Genetics Society of Australasia (2010) recommends that couples planning or in the early stages of pregnancy be made aware of the availability of CF carrier screening

Program Development 2005  

2006  

2007  

Working  group  

Pre-­‐pilot  

Pilot:  private  pracDce  

State-­‐wide:  shared  care    

General  pracDce  

Expanded  program:  -­‐  more  mutaDons    -­‐  more  condiDons  

2013  

How the CF screening program worked •  Pre-pregnancy or prenatal

screening offered by obstetrician or GP

•  Pre-test information •  Obstetrician/GP •  Brochure in test pack •  Website

•  Testing by cheek brush •  Self-administered •  12 CFTR mutations

•  Posted to laboratory •  Cost: $200 per test

The first 7 years experience •  Number screened: 10,489

•  Approx 90% females •  Number carriers: 320 (3.05%; 1 in 33)

•  83% deltaF508 mutation •  Number carrier couples: 15

•  11 pregnant at time of screening •  9 chose prenatal diagnosis •  3 affected pregnancies •  All carrier couples chose prenatal diagnosis or preimplantation

genetic diagnosis in subsequent pregnancies •  1 false negative result (missed case)

•  parents screened as low risk – child with CF due to paternal uniparental disomy of chromosome 7

(Archibald et al., Medical Journal of Australia 2014)

VCGS expanded approach VCGS Reproductive screen

•  CF •  SMA •  Fragile X

These disorders are •  Common •  Severe •  Tests relatively sensitive and

specific •  Mature technology

Cost to patient AU$385

Diseases screened Cystic fibrosis

CF is an inherited condition affecting breathing and digestion. CF causes thick mucus which traps bacteria, resulting in recurrent infections that damage the lungs. Until recently, many children with CF died in early childhood

but now many live to be 30, 40 or more. There is no cure for CF but better treatments are under research and development.

Fragile X syndrome

FXS is the most common cause of inherited intellectual disability. People with FXS can have developmental delay,

learning difficulties, anxiety, autism and epilepsy. The features of FXS vary from mild to severe with males more likely to be severely affected than females. There is no cure for FXS although some interventions can improve outcomes for people with FXS. Some females who are carriers of FXS may have early menopause.

Spinal muscular atrophy

SMA is a condition that affects nerves in the spinal cord and causes muscles to get weaker. There are four types of

SMA. SMA type 1 is the most severe. Babies with SMA type 1 have weak muscles from birth and usually do not live past 2 years of age. SMA types 2 and 3 progress more slowly than type 1. There is no cure for SMA, however

there are treatments and interventions available aimed at managing symptoms and improving quality of life.

The future - expanded carrier testing •  We are all carriers of 5-10 autosomal

recessive mutations •  Theoretically it should be possible to

screen all couples prior to pregnancy to identify these mutations

•  Offer prenatal diagnosis or PGD to couples who both carry a mutation in the same gene

•  Current obstacles = •  Cost •  Interpretation

Target  Enrichment  (e.g.  Exome,    gene  panels)  

Whole    genome    

Counsyl test (Srinivasan et al., 2010; Lazarin et al. 2013) •  108 genetic diseases, 417 causal disease variants

•  Includes many ethnic specific mutations •  For ¼ of diseases, sensitivity is <10% of all mutations •  For ½ of diseases, sensitivity is <50% •  High specificity (>99.6%) – if something is detected, it is likely to be

real •  Can either test one partner first (two-step) or both simultaneously

(one-step) •  1 in 4 patients receive abnormal result

•  Test cost AU$849 (with Fragile X) through Healthscope

Counsyl test in practice (Lazarin et al. 2014) •  23,453 patient screened •  417 mutations associated with 108 conditions •  5,633 (24%) received were carriers for at least one condition (1 in 4.2) •  127 carrier couples

•  47 alpha-1 antitrypsin deficiency •  27 CF •  15 SMA •  10 sickle cell disease •  3 Ashkenazi •  = 102 would have been detected using existing testing including

VCGS RGCS

Compared to VCGS RGCS, need to screen about 1000 people to detect one extra carrier couple!

723  variants  in  147  genes    All  of  147  genes    

Emory  

…..or the “Rolls-Royce”

Choosing the right test

Single  gene  e.g.  CF  $150  

VCGS  3  disorder  screen  $385  

Counsyl,  Emory  targeted  

muta@on  panel  100-­‐150  genes  $900-­‐$1700  

Emory  sequencing  

panel  150  genes  

$2000-­‐$4000  

Whole  genome  • 22,000  genes  and  all  in  between  

• $14k-­‐$28k  

Criticisms of extended carrier screening •  Marketing direct to patients •  Lack of supportive clinical guidelines •  Do not meet generally accepted criteria for population screening

•  (many conditions rare, not severe, natural history not understood) •  Depending on approach, there will always be:

•  False negatives (low sensitivity) or •  False positives (low specificity)

•  Follow up testing and counselling likely to be expensive •  Psychological impact significant •  Inclusion of some common mild disorders inflates data •  Lack of public funding

Stoll and Resta, Genetics in Medicine 2013