Susceptibility: Newborn Screening

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SusceptibilityNewborn Screening

• Edward RB McCabe, MD, PhD
• Physician-in-Chief, Mattel Childrens Hospital
  UCLA
• Mattel Executive Endowed Chair of Pediatrics
• Professor of Pediatrics, Human Genetics, and
  Bioengineering
• Co-Director, UCLA Center for Society and Genetics

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Overview Newborn Screening(NBS)

• Highest Volume Genetic Testing
• Laboratory for Personalized Medicine
• Lessons from Expanded NBS
• Future Directions in NBS

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Highest Volume Genetic Testing
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Newborn Screening

• The developed world has had population based
  screening since the 1960s
• Newborn screening is a model for
  genomic medicine
• Nearly every newborn in the developed
  world is screened for genetic
  and other congenital diseases using
  relatively inexpensive laboratory
  methods

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Newborn Screening

• All states and the District of Columbia screen
  the 4 million newborns each year for six
  disorders
• - Phenylketonuria (PKU)
• - Congenital hypothyroidism
• - Galactosemia
• - Sickle cell disease and other
  hemoglobinopathies
• - Congenital adrenal hyperplasia (CAH)
• - Maple syrup urine disease (MSUD)

Data updated 3-11-09 http//genes-r-us.uthscsa.ed
u/nbsdisorders.htm
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Newborn Screening

• Each state has its own newborn screening program
• Depending on the state of birth, a newborn can be
  screened for 9-42 disorders
• The American College of Medical Genetics (ACMG)
  recommends newborn screening for 29 disorders

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Newborn Screening

• The March of Dimes would like every baby to be
  screened for the 29 disorders that the ACMG
  recommends
• Each year the March of Dimes publishes a newborn
  screening report card
• 2008 report card
• 25 states and the District of Columbia screened
  for all 29 disorders

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Newborn Screening Tests
Source March of Dimes. Data reported from NNSGRC.
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NBS Highest Volume Genetic Testing

• In the US
• 4M births/yr
• 29 ACMG core diseases
• 116M genetic diseases tested/yr
• 25 ACMG secondary targets
• 100M genetic diseases tested/yr
• Total 216M genetic diseases
• tested/yr

McCabe and McCabe, DNA Promise and Peril, 2008
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NBS Highest Volume Genetic Testing

• Internationally
• 25-30 of the worlds 133 newborns undergo
  newborn screening
• 33-40M babies/yr
• 54 core and secondary target diseases
• Would result in 1.8-2.2B genetic diseases
  tested/yr
• Number increasing

McCabe and McCabe. Ann Rev Med 59163-175, 2008
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Laboratory for Personalized Medicine
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Personalized Medicine

• Medical practice today
• - Acute intervention when a
  clinical condition presents suddenly and
  unexpectedly
• - Patients with chronic illness are surviving
  and their complications are neither sudden nor
  unexpected, but their complications
  are often addressed
  acutely

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Personalized Medicine

• The current culture of medicine is based on acute
  intervention, and health care attracts those who
  are action oriented and desire immediate
  gratification
• Personalized Medicine will be
• - Predictive
• - Preventive

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Personalized Medicine

• We will need to go beyond an
  individuals genomic sequence
• Must consider phenotypic consequences of
  
• Interactions within the genome
• Modifier genes
• Between the genome and
  environment
• Epigenetics
• Need to learn to integrate across xomics

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Personalized Medicine

• We will need to screen large populations
• To identify individual differences
• To be able to predict disease predispositions
• To attempt to prevent the consequences
• Will require massive bioinformatic capacity
• To analyze genomic data
• To integrate xomic data

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NBS Parallels with Personalized Medicine

• Involves large populations
• All newborns
• Predictive
• Identifies affected newborns
  before they exhibit phenotype
• Preventive
• Intervene early to prevent the onset or
  progression of symptoms

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NBS Lessons Learned

• Phenotypes invariably broadened when
  ascertainment is by lab criteria
• Clinical evidence-base should be driver for
  inclusion of targets and testing technologies
• Expansion should be
  well-planned and rational

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Lessons from Expanded Newborn Screening
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Tandem Mass Spectrometry (MS/MS)
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Newborn Screening

• Tandem Mass Spectrometry (MS/MS) is two molecular
  fragmentation steps that identifies signature
  metabolites for more than 30 genetic metabolic
  diseases
• Medium Chain Acyl-CoA Dehydrogenase (MCAD)
  Deficiency
• Disorder of fat metabolism
• Viral illness leads to low blood
  sugar, seizures and coma

20 month old with MCAD deficiency
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MS/MS Lessons Learned

• Early mortality decreased and symptoms less
  severe compared to clinical diagnosis
• Cost per quality-adjusted life year (QALY) in
  worst case scenario for CA
• 11-19,000
• Cost/QALY lt50,000 is cost effective
• States attempted to establish
  cut-off criteria independently

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Future Directions in NBS
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Dramatic Expansion of Newborn Screening
Anticipated

• Technology is available
• Tandem mass spectrometry with addition of 30
  diseases has set precedent
• Would benefit from a consolidation of platforms
• Patients with numerous
  diseases could benefit
  from early detection
• NBS for SCID is one
  example

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NBS for Severe Combined Immunodeficiency (SCID)
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NBS for SCID

• X-linked recessive disorder (up to 50)
• Males with severe infections
• Overall SCID incidence
• Estimated 1/50,000-100,000
• Probably under-diagnosed since the cause of death
  is overwhelming infection

David P Vetter 1971-1984
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Effective Treatment Available for Patients with
SCID

• Fatal if untreated
• Effective treatment is available
• Hematopoietic stem cell therapy
• At least 75 survival overall
• Up to 95 survival if treated in first month of
  life
• Therefore, NBS for SCID is required for effective
  intervention

7 mo S/P bone marrow transplant from mother
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NBS for SCIDMcGhee et al. MGM 86427, 2005

• Technology exists for SCID NBS
• Assay for T-cell
  recombination receptor
  excission circles (TRECs)
• First example of primary
  DNA assay
• Wisconsin began
  SCID NBS on
  January 1, 2008

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Cost-Benefit Analysis McGhee et al. J Pediatr
147603-608, 2005

• SCID NBS
• 53,560/QALY (Qual Adj Life Year)
• Cost lt5/test
• False neg 0.9
• False pos 0.4
• 23.9M/yr for US
• 80 children detected/yr
• 760 yr of life saved/yr of screening
• 485K/SCID detected

• Comparison
• Sickle cell disease
• 13K/QALY
• Tandem mass spec
• lt42K/QALY
• Prostate cancer
• gt100K
• Carotid artery stent
• gt100K/QALY

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SCID Newborn Screening

• Significant benefit to detected individuals
• Acceptable cost-effectiveness despite low
  incidence of SCID
• Adequate test is critical to cost-effectiveness
• Research project with the Navajo Jennifer Puck,
  UCSF

SCID 1/2,000 among the Navajo
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Whole Genome Analysis in Newborn Screening
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Microarray-Based Testing Devices

• Roche AmpliChip CYP450
• Approved by FDA January 12, 2005
• First microarray-based testing
• Affymetrix 250K SNP chip approved by FDA and 1M
  SNP chip pending

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Molecular Cytogenetics

• DNA is stable in and can be eluted from dried
  blood spots
• Single nucleotide polymorphism microarrays (SNP
  chips) can determine copy number variations
  (CNVs)

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Cytogenetic Abnormalities

• Compared to other disorders identified by NBS
• Very high frequency
• 1/160 live born infants
• For many, no definitive therapy
• But consider Down syndrome

Rosewood State Hospital, MD
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Whole Genome Data Is Acquired

• Patient below without any known genetic disease
• All chromosomes but Y represented

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Multiple Patients with del22q11.2 Syndrome Show
Similar Deletions in DGCR

• Five patients with del22q11.2 show similar 3 Mb
  TDR
• Not seen in five patients without del22q11.2
  syndrome

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CNVs Are Common in All Genomes Surveyed
CNV differ between identical twins Dumanski et
al. Am J Hum Genet 82763, 2008

• Blue pathogenic
• Red deletion
• Green duplication

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SNP Chip Technology

• Allows examination of DNA and not chromosomes
• Will permit newborn screening for cytogenetic
  abnormalities
• But serious ethical, legal and social
  implications associated with this

www.socgen.ucla.edu/
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SNP Chips gt Sequencing

• SNP chip technology is setting the stage for
  whole genome sequencing
• Learning to deal with
• Massive data-sets
• Uncertainty
• Human Genome
  Project will impact
• NBS
• Personalized
  Medicine

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