Transcript Carrier Screening with Next Generation DNA Sequencing 2014

Carrier Screening in ART 2014
The Value of Next-Generation DNA Sequencing
Stephanie Hallam, PhD, FACMG, MBA
VP Laboratory Operations & Medical Director, Good Start Genetics
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Agenda
• Need for Carrier Screening
• Responsible Approach
- Clinically relevant tests
- Best in class technologies
• The Need for Accurate Screening
• Value of Next-Generation Sequencing Technology
• Clinical Experience
- Clinical benefits of sequencing-based assay
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The Need for Carrier Screening
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Importance of Carrier Screening
• Recommended by leading medical societies
-
ACOG
ASRM
ACMG
Jewish advocacy organizations (e.g., NTSAD)

Disorders should be prevalent, have severe forms, and
be costly to treat
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The Need for Better Screening
• 1/100 babies are born with an inherited
disease1
• 20-30% of all infant deaths are due to
genetic disorders2
• 11.1% of pediatric hospital admissions
are for children with genetic disorders3
• Preconception screening for disease-causing mutations
and genetic counseling for carriers can reduce the
incidence of these diseases
• Incidence of Tay Sachs disease was reduced by 90% in
AJ due to awareness and screening4
1 Monogenic disorders, World Health Organization
2 Berry, et al, 1987
3 Scriver, et al, 1973
4 Kaback, et al, 2000
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Cystic Fibrosis (CF)
•
CF is the most common lifethreatening, genetic disorder in
Caucasians
• Despite widespread availability of carrier
screening, more than 2,500 babies are
born with cystic fibrosis each year
• The average survival age is late 30’s¹
• Individuals with CF endure chronic
symptoms with lifetime treatment costs
estimated over $2,000,000¹
• 1 in 25 Caucasians is a carrier of CF
¹CF foundation website
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Spinal Muscular Atrophy (SMA)
•
SMA is the leading genetic
cause of death in infants and
toddlers.
• 1/6,000 to 1/10,000 children are
born with the disease
• The most severe form (Type I)
manifests before 6 months of age
and generally results in death
before age two
• One in 40 to one in 50 people
(approximately 6 million Americans)
are carriers of the SMA gene.
Spinal Muscular Atrophy (SMA) is a
genetic neuromuscular disease
characterized by muscle atrophy
and weakness.
Data from SMA foundation website
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Carrier Screening:
Assessing Inherited Disease in Couples
• Helps determine risk for
conceiving a child with an
inherited disease
• About 1 in 16 Caucasians is a
carrier for cystic fibrosis or
spinal muscular atrophy, the
most common autosomal
recessive diseases.
• Preconception carrier
screening for pathogenic gene
mutations and genetic
counseling can reduce the
incidence of disease
Fragile x syndrome does not follow this
inheritance pattern.
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Pre-Pregnancy Screening Provides Valuable
Early Information
Pre-Pregnancy
Screening
Multiple options
• Proceed at-risk
•
Prenatal testing
• IVF with preimplantation genetic
diagnosis (PGD) of
embryos
• Sperm or egg donation
• Adoption
Prenatal
Screening
• Preparation, genetic
counseling, support
groups
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Newborn
Screening
• Early detection
enabling early
treatment, genetic
counselor, support
groups
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Responsible Approach
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A Balanced Approach to Genetic Screening
Testing for society guideline recommended disorders using a
comprehensive set of disease-causing mutations
Society
Guideline
Recommended
Disorders
Balance drives clinical value and sets
the new standard for excellence
Prevalent & Severe
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DiseaseCausing
Mutations
Validated Pathogenicity
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Guideline and Society-Recommended Disorders
Disorder
Recommended by:
Jewish
ACOG ACMG Societies
Common Disorders
Cystic Fibrosis
Focus on society-recommended
disorders:
- Provides clinicians confidence
that they are screening for
relevant diseases
Fragile X Syndrome*
Spinal Muscular Atrophy
Hemoglobin Diseases
Alpha-Thalassemia
- Assures payers that testing is
justifiable
Beta-Thalassemia
Sickle Cell Disease
Ashkenazi Jewish Disorders
Canavan Disease
Familial Hyperinsulinism
Familial Dysautonomia
Glycogen Storage Disease Type Ia
Tay-Sachs Disease**
Joubert Syndrome 2
Bloom's Syndrome
Maple Syrup Urine Disease Type A/B
Fanconi Anemia Group C
Nemaline Myopathy
Gaucher Disease
Usher Syndrome Type IF
Mucolipidosis Type IV
Usher Syndrome Type III
Niemann-Pick Disease Type A/B
Walker-Warburg Syndrome
Dihydrolipoamide Dehydrogenase Deficiency
* Recommended if indicated by family history
** Recommended for individuals of French Canadian or Cajun descent
AJ – Tests recommended by national Jewish advocacy societies.
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The Best Technology for Each Test
Test Methodology
Next-Generation DNA Sequencing
(comprehensive)
Next-Generation DNA Sequencing
(targeted)
Multiplex Ligation-Dependent Probe
Amplification (MLPA)
Tri-Nucleotide Repeat PCR &
Methylation Analysis
Enzyme Analysis
Hemoglobin Capillary Electrophoresis
Genotyping
Disorder(s)
Bloom’s syndrome
Canavan disease
Cystic fibrosis
DLD deficiency
Familial dysautonomia
Familial hyperinsulinism
Fanconi anemia group C
Joubert syndrome 2
Walker-Warburg syndrome
Alpha-thalassemia
Spinal muscular atrophy (SMA)
Glycogen storage disease 1a
Maple syrup urine disease 1A/1B
Mucolipidosis type IV
Niemann-Pick type A/B
Tay-Sachs disease
Usher syndrome type 1F
Usher syndrome type III
Fragile X syndrome
Tay-Sachs disease (Hex A)
Beta-thalassemia
Sickle cell disease
Gaucher disease
Nemaline myopathy
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The Need for Accurate Screening
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Why is Accurate Screening Important?
Screen with ~100 mutations
Result = Negative
Not tested because
partner is negative
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Why is Accurate Screening Important?
Child affected
with cystic
fibrosis
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Why is Accurate Screening Important?
Carrier of a rare
mutation, not detected
by test that was used
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Carrier of a
common mutation,
but not tested
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Why is Accurate Screening Important?
Carrier
Carrier
identified by test
with higher
detection rate
identified because
his partner
screened positive
1 in 4 chance for
each pregnancy to
be affected
Reproductive Options Available
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Next-Generation DNA Sequencing
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DNA Sequencing: The “Old” Way
• First human genome
- ~13 years
- ~ $3B
• At completion, cost to repeat
was $300M
• Routine clinical sequencing
was unaffordable
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Next-Generation DNA Sequencing
• Massively parallel
chemistry and detection
- Faster
- Cheaper
• Revolutionizing Clinical
Molecular Testing
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Next-Generation Sequencing: Technology Matters
• Genotyping
•
•
•
Used by many companies for routine carrier screening
Tests for a limited set of only common mutations
Provides limited utility beyond Caucasian and Jewish ethnicities
• Next-Generation Sequencing
•
•
•
Comprehensively evaluates the gene
Detects all known common and rare disease-causing mutations
Delivers higher accuracy across ethnicities
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Delivering Clinically Actionable Results
Comprehensive Set of Known Disease-Causing
Mutations
• Rigorous, multi-year process to catalogue and evaluate
each gene for all documented disease-causing variants
• Accurate, actionable results that do not include variants
of unknown significance (VUS)
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Evaluating Variants: Not all are pathogenic
• Some have no
detrimental effect
• Some have a mild
effect
• Some cause severe
disease
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Mutation Database: Validating the Variants
>2,700 variants
• Literature (PubMed)
• Locus Specific Databases
Genetic Evidence
Experimental
Evidence
Sequence Based
Evidence
~ 1,700 variants
~1,000 variants
classified as
disease-causing
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NGS Versus Genotyping:
Mutations in the CFTR Gene
Each dot represents a
disease-causing mutation.
(illustrative purposes only)
ACMG 23
Standard genotype
screening panels (≈100)
Previously publicly reported
pathogenic mutations (550)
Novel truncating mutations
detectable by next-generation
DNA sequencing (unknown)
GoodStart Select™ detects all of the
disease-causing mutations above
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The Power of Sequencing
NGS Tests for 5-10 Times More Pathogenic Mutations Per
Disease than traditional genotyping
DISEASE
Bloom's Syndrome
Canavan Disease
Cystic Fibrosis
Dihydrolipoamide Dehydrogenase Deficiency
Familial Dysautonomia
Familial Hyperinsulinism
Fanconi Anemia Group C
Glycogen Storage Disease Type 1A
Maple Syrup Urine Disease Type 1A/1B
Mucolipidosis Type IV
Niemann-Pick Disease Type A/B
Tay-Sachs Disease
Usher Syndrome 1F
Usher Syndrome III
CARRIER
FREQUENCY*
LEADING 1
COMPETITORS
GOOD START 3
GENETICS
1 in 134
1 in 55
1 in 23
1 in 107
1 in 31
1 in 68
1 in 100
1 in 64
1 in 97
1 in 89
1 in 115
1 in 27
1 in 147
1 in 120
1-2
4
~ 100
0-2
2 - 32
0-3
2-4
2 - 10
3-4
2
3-4
7 - 11
0-1
0-1
51
44
560
3
2
65
26
69
40
9
45
73
16
5
1 Data on file as of 12/2013.
2 Third mutation reported by one competitor not confirmed by GSG to be of clinical significance.
3 According to most-recently updated version of the GSG mutation list (9/13/2013).
* Based on Ashkenazi Jewish population (population selected because figures are available for all disorders).
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Updated 5/2014
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Mutations Reported
Common
Mutations
Uncommon
Mutations
• Previously reported in the
literature
• High frequency
In Validated Database
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Mutations Reported
Traditional genotyping tests for a limited set of mutations.
Carrier screening by genotyping
Common
Mutations
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Uncommon
Mutations
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Mutations Reported
Good Start’s NGS test for 5-10 times more mutations than carrier
screening tests performed by genotyping.
Carrier screening by next-generation DNA sequencing
Common
Mutations
Uncommon
Mutations
Novel
Mutations
Truncating mutations
expected to disrupt
protein function
Any two mutations from the same disorder can cause disease
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Detection of New Pathogenic Mutations
NGS enables the discovery of rare and novel mutations in a
pan-ethnic population
Case Study: New CFTR Mutation Found Using NGS
Normal
Normal working protein
Truncating
Mutation
Definition of Novel:
• Not yet described in the literature
• Disrupts protein structure and will cause disease
Protein is cut off and does
not work properly
*Data presented at the 2013 Annual Meeting of the Pacific Coast Reproductive Society
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Clinical Experience
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Clinical Experience
• 22,296 patients from infertility
centers across the US
• Screened for up to 14 disorders
using next-generation DNA
sequencing
• Carrier status determined by the
presence or absence of a pathogenic
mutation
Self-reported
Ethnicity
% of Total
Caucasian
44.7%
Not Provided
29.0%
African American
7.0%
Asian
6.3%
Hispanic
5.8%
Other
4.8%
Ashkenazi Jewish
2.5%
• Analysis of results: Good Start’s NGS
versus genotyping-based carrier
screening tests
Data up to 1/31/2014
.
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Carriers Detected
Carriers Detected
Genotyping
Assays
GSG Only
Familial Hyperinsulinism
23
7
Canavan Disease
36
6
Maple Syrup Urine Disease Type 1A/1B
18
14
Bloom Syndrome
13
20
Cystic Fibrosis
952
51
Usher Syndrome Type III
9
4
Dihydrolipoamide Dehydrogenase Deficiency
13
2
Fanconi Anemia Group C
23
9
Glycogen Storage Disease Type 1a
36
5
Tay-Sachs Disease
87
18
Familial Dysautonomia
34
9
Mucolipidosis Type 1V
15
8
Usher Syndrome Type IF
9
10
Niemann-Pick Disease Type A/B
26
6
1294
169
Total
Gene
~12% of
carriers would
not have been
identified using
genotypingbased carrier
screening1,2
Total
Carriers
30
42
32
33
1003
13
15
32
41
105
43
23
19
32
1463
1 – Results based on analysis of 22,296 patients in IVF centers across the country screened for up to 14 disorders using GoodStart Select.
2 – Analysis was done by comparing the mutations found using GoodStart Select to competitors’ genotyping panels. If all competitors did not test
for a particular mutation, then it was marked as GSG only.
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Clinical Implications of NGS for Your Patients
Reduce the risk of having a child with a
common, severe genetic disorder
High detection rate, regardless of ethnicity
Low residual risk, regardless of ethnicity
Confidence in a negative test result
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Thank You!
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