Overview Molecular Newborn Screening
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Overview Molecular Newborn Screening
Michele Caggana, Sc.D.Director, Newborn Screening Program
New York State Department of HealthWadsworth Center
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Wadsworth CenterORNL
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Human Genome Project
Proposed by Victor McKusick in 1968
DOE and NIH, 15 years, 30 billion dollars
James Watson original head then Francis Collins
International effort
ELSI budget
Wadsworth Center
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Human Genome Project
Five Main Objectives:
1. Generate genetic and physical maps
2. Develop new DNA technologies
3. Accurately sequence the human genome
4. Develop informatics
5. Sequence model organisms
Wadsworth Center
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Human Genome Project
Accurate Sequence Data:3,000,000,000 bases; haploidRough draft / 90%, summer 2000, 2/01
”finished”Highly accurate (1 error in 100,000 bases) no gaps or ambiguities by 2003
First chromosome 22 reported 12/99chromosome 21 reported 5/00
Projected finish 2003, original 2005Wadsworth Center
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Wadsworth Center
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Venter & Collins
Private vs. Public
Wadsworth Center
1000 Genomes Project
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Genetics is the study of heredity. It examines a small number of genes, and how they are inherited in families with disease.
Genomics is the study of theentire DNA instruction set.
23 pairs of chromosomes3.1 billion bases
“We are 99.9% identical”--Bill Clinton
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Linkage:Uses recombinationRequires multiple families with diseaseRequires the investigator to choose a model of inheritance
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Association StudiesNon-related, subject to bias
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From: http://www.dadamo.com/wiki/hapmap.jpg
A. SNPS : ~10 million total
Chromosome 1 AACACGCCA.…TTCGGGGTC….AGTCGACCG….
Chromosome 2 AACACGCCA….TTCGAGGTC….AGTCAACCG….
Chromosome 3 AACATGCCA.…TTCGGGGTC….AGTCAACCG….
Chromosome 4 AACACGCCA.…TTCGGGGTC….AGTCGACCG....
B. HAPLOTYPES
Haplotype 1 C T C A A A G T A C G G T TC A G G C A
Haplotype 2 T T G A T T G C G C A A C A G T A A T A
Haplotype 3 C C C G A T C T G T G A T A C T G G T G
Haplotype 4 T C G A T T C C G C G G T T C A G A C A
C. Tag SNPs: far fewer A / G C / T C / G
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Factors Affecting Risk and Strengths of Association and NBS
Was the disease defined accurately?
Was the relatedness of the population described?
Could genotyping errors affect results?
Is the test population the same as the reported population, i.e. ancestry? (population stratification)
Was there ascertainment / selection bias
Was environmental exposure variability considered?
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Distinction Between Mutations and SNPsMutations: Changes in the DNA, which are ‘rare’; can be private; newer
SNPs/Polymorphisms: Changes in the DNA occurring at a higher frequency, usually greater than 1%; may start as mutations and reach a higher frequency; older changes.
Both are inherited and can be used to track DNA changes
cSNPs are in the coding regionsynonymous: no change to the amino acid (silent)non-synonymous: change to the amino acid
Non-coding SNPs: promoter, splice sites, stability, other regulatory changes
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Improvement of the Literature
Collect data, clinical followup
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• NormalCCG GGA AGC AAUPro Gly Ser Asn
• MissenseCCG GCA AGC AAUPro Val Ser Asn
• NonsenseCCG UGA AGC AAUPro STOP
TYPES OF MUTATIONS
Wadsworth Center
• Frameshift (insertion)CCG AGG AAG CAAPro Arg Lys Gln
• Frameshift (deletion)CCG GAA GCA AUGPro Glu Asp Met
• TrinucleotideCAG CAG CAG CAGGln Gln Gln Gln
Mutations can be helpful – camouflage; selectionMutations can be silent –markers, forensics, mapping, population studiesMutations can be harmful – sickle cell, PKU, CF and other diseases
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Genetic Disorders
Caused by mutations in genes or chromosomes
Mutations may occur on: -- An autosome (autosomal)-- A sex chromosome (X-linked or Y-linked)-- Multiple genes
Disease expression may be impacted by environmental factors
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Single Gene Disorders
Caused by mutations in one geneGenerally follow Mendelian inheritance
patterns-- Dominant vs. Recessive-- Expression may be impacted by genomic
imprinting or penetranceIncludes most inborn errors of
metabolism
Most “single gene disorders” are probably influenced by multiple genes / DNA
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Classes of Single Gene Disorders Autosomal Dominant
One copy of a mutated allele results in affected individualaka: AA or AaHeterozygous and homozygous individuals are affectede.g. achondroplasia, Huntington disease
Autosomal RecessiveBoth copies of the gene must be mutated to be
affectedaka: aaOnly homozygous individuals are affected.e.g. Sickle cell anemia, cystic fibrosis, galactosemia
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Classes of Single Gene Disorders X-linked Recessive
-- Males affected if X chromosome is mutated-- Females affected only if both X chromosomes are
mutated; e.g. Duchenne muscular dystrophy & hemophilia
X-linked Dominant-- Individuals with 1 mutant copy of X chromosome
are affected; e.g. Rett syndrome Y-linked
-- Individuals with a mutated Y chromosome are affected
-- Rare
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Complex / Multifactorial Disorders
Associated with small effects of multiple genes
May be strongly impacted by environmental factors (e.g. lifestyle)
Familial clustering-- No clear-cut pattern of inheritance-- Difficult to determine risk
Heart disease, diabetes, obesity, cancer
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Molecular Testing for Genetic Diseases
• Enabled by gene mapping to identify location of genes on chromosomes AND ability to differentiate between harmful and neutral mutations
• Identification of disease-causing mutations for:– Diagnosis – Predictive testing– Carrier detection– Prenatal screening– Preimplantation testing– Pharmacogenetics
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Availability of Genetic Tests
610 Laboratories offering in-house molecular genetic testing, specialized cytogenetic testing, and biochemical testing for inherited disorders
2612 Diseases2355 Clinical257 Research
GeneTESTS: Availability of Genetic Tests
As of 5/1/2012, http://www.ncbi.nlm.nih.gov/sites/GeneTests/
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Availability of Genetic Tests
As of 5/1/2012, http://www.ncbi.nlm.nih.gov/sites/GeneTests/ site is being revised
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Firm Brings Gene Tests to Masses (NYT)Published: January 28, 2010 REDWOOD CITY, Calif. — The new movie “Extraordinary Measures” is based on the true story of a father who starts a company to develop a treatment for the rare genetic disease threatening to kill two of his children before they turn 10……
What condition??
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History of Molecular Testing in Newborn Screening
1994-- Washington – hemoglobin confirmatory
testing (Hb S, C, E by RFLP)-- Wisconsin – CFTR mutation analysis for
DF5081998
-- New England – 2 GALT mutations (Q & N) by RFLP
1999-- New England – MCADD (c.985A>G) by RFLP
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History of NBS Molecular Testing2005
-- Wisconsin – MSUD (p.Y438N)2006
-- New York – Krabbe disease (3 polymorphisms & 5 mutations; full gene DNA sequence analysis)
2008-- Wisconsin – SCID – TREC analysis
1st use of molecular test as a primary full population screen
2010-- 36 NBSPs in US use molecular testing for CF
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Uses of Molecular Tests in NBS
Primary Screening Test-- TREC analysis for detection of SCID
Second-Tier Test-- DNA test results provide supplemental
information to assist with diagnosis-- Often provided in separate report-- b-globin and GALT mutation analysis
Genotypic information is required for interpretation of the screen result
-- Cystic fibrosis mutation analysis
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Things for Programs to Consider2nd tier v. 1st tier
Which tests will have a molecular component?
DNA extraction methods; (cost/labor)
Degree of automation; vendors and contracts
Manipulation (single tube? 96-well? 384-well?)
# Instruments, data collection, interpretation
Staff training (lab and follow-up)
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NBS Molecular Tests in US
Primary screen -- SCIDSecond-tier screen
-- Hemoglobinopathies-- Galactosemia-- Cystic fibrosis-- MCAD and other FAOs-- Phenylketonuria-- Krabbe disease-- Maple syrup urine disease
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Does Molecular Testing Add Value??
Increase in sensitivity of a primary test, effect on specificity?
Identification of carriers; teaching momentsPredictions regarding phenotype
Clinicians’ perception, diagnostic tool
OR
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When / Why Use a Molecular Test?
To increase sensitivity without compromising specificity-- Lower IRT cutoff to avoid missing CF cases
To increase specificity of a complex assay-- Allow differentiation of hemoglobinpathies &
thalassemias (e.g. Hb S/b-thalassemia)
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When the primary analyte is transient-- The primary analyte is present for only a limited
time after birth and analysis of a second specimen could result in a false negative. (e.g. VLCAD / CPT2)
To speed diagnosis in order to avoid serious medical consequences-- GALT enzyme activity is decreased by heat &
humidity, increase in false positive screens -- Genotyping helps sort out the true positives for
faster diagnosis.
When / Why Use a Molecular Test?
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When there are significant founder mutations in a population
-- Due to high frequency (1 in 176 live births) of MSUD in Mennonite population in WI, mutation analysis for p.Y438N serves as primary screen for MSUD for Mennonites.
-- CPT1a in Alaskan Inuit & Hutterite populations
When / Why Use a Molecular Test?
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When diagnostic testing is slow and/or invasive-- Traditional confirmatory testing for VLCAD
& CPT1a involves skin biopsy (invasive to collect and slow to grow)
When no other test exists for the analyteSCID, SMA
When / Why Use a Molecular Test?
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Things for Programs to ConsiderBy Contract
Which tests will have a molecular component?
Specimen transport
Screening or confirmatory?
Timing and prioritization for contract lab
Systems integration
Follow-up integration
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Things for Programs to ConsiderIn-House 1
Volume / quality of specimensCost ($$$) per sample“Simple test” mentalityPublic health infrastructure
-- Equipment-- Space
ELSIHave test, no Tx
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Capacity – Throughput -- Automation?
IVD v. ASR / LDT;
Expertise / Interpretation
Methods / Manipulation – single tube? 96-well or 384-well plates
Control Materials
Integration into Program / LIMs / Follow-up / TAT
Things for Programs to ConsiderIn-House 2
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Make copies (extend primers)
Starting DNA Template
5’
5’
3’
3’
5’
5’
3’
3’
Add primers (anneal) 5’3’
3’5’
Forward primer
Reverse primer
DNA Amplification with the Polymerase Chain Reaction (PCR)
Separate strands
(denature)
5’
5’3’
3’
www.nist.gov
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In 32 cycles at 100% efficiency, 1.07 billion copies of targeted DNA region are created
PCR Copies DNA Exponentially through Multiple Thermal Cycles
Original DNA target region
Thermal cycleThermal cycleThermal cycle
www.nist.gov
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Thermal Cyclers (PCR machines)
Compliments of Colleen Stevens Wadsworth Center
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http://www.nature.com/nmeth/journal/v2/n12/images/nmeth1205-989-I2.jpg
5 million SNP markers
IlluminaTechnology
BeadArray
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Gel Electrophoresis
Large
SmallAnode
CathodeDECREASING
SIZE
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ctcctg a ggagctcctg t ggag
Dde I
tt
t
c
cc
Wadsworth Center
Restriction Fragment Length Polymorphism (RFLP)
CTNAGGANTC
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Allele Specific Oligonucleotide Hybridization (ASOH)
-80 G to A (IL-5R)tgcctgaga g tttttaa-32Ptgcctgaga a tttttaa-32P
Mutantnormal mutant
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Wadsworth Center
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Multiplex PCR• Many genes can be copied at
once• Sensitivities to levels less than
1 ng of DNA• Different fluorescent dyes used
to distinguish alleles with overlapping size ranges
www.nist.gov
Gene 1Gene 2Gene 3Gene 4
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Taq Man – Targeted SNP Assays
Each SNP is engineered as a separate reaction.
Probes have quencher linked to the fluorescent reporter.
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Potential Future Applications of Molecular Testing in NBS
Expansion to other existing or potential NBS disorders– Congenital adrenal hyperplasia (CAH)– Biotinidase deficiency– Ornithine transcarbamylase deficiency (OTC)– Cytomegalovirus– Fragile X syndrome– Duchenne muscular dystrophy (DMD)– Lysosomal storage disorders (LSD)
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Potential Future Applications of Molecular Testing in NBS
Genome-wide association studiesSusceptibility testing (heart disease,
cancer, obesity, diabetes)Next generation sequencing - exome,
genome and transcriptomePharmacogenetics and NBS
-- Drugs in clinical trials to treat specific CF causing mutations (VX-770/G551D and VX-890 / DF508)
-- Ataluren (formerly PTC124) is an investigational drug that reads through nonsense or STOP mutations
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Mix deoxynucleotides with ddA, ddT, ddC*, ddG4 lanes per person/fragment~200 readable bases
Mix deoxynucleotides with ddA, ddT, ddC*, ddG1 scan per person/fragment~800 readable bases
Chop up the human genomeMake a library of fragmentsSequence billions of basesMultiplexing multiple peopleMillions of ‘reads’
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Evolution of Krabbe Disease Screening
Pan-ethnicFrequency 1:100,000 worldwideGene described in 1993Prenatal screening 80’s by enzyme,
molecular 90’sNew York 8/7/06; 1.75 million screened; MO 1
yearLegislation pending (NM, IL, NJ)
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State of NBS for Krabbe Disease
Full gene sequence required~25 novel variants have been detected in
screeningCommon complex genotypesVariants of unknown significanceOne mutation, no enzyme activityTwo mutations, asymptomaticTwo mutations, different phenotypesParental anxiety
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Krabbe Today Mimics CF Yesterday No population / carrier screening Molecular data from symptomatic, infantile No common panel, except 30Kb deletion No natural history from a screened population Information will drive treatment Information will develop evidence base Policy will follow Will we ever get to the ‘common’ mutation
panel??
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