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CAN GENETIC STUDIES HELP TO BETTER
UNDERSTAND & TO REDUCE RISK FOR
SIDS?
Carl E. Hunt, MD
First Candle Symposium
March 24, 2009
OBJECTIVES


Review Genetic Risk Factors for sudden,
unexpected deaths in infancy (SUDI)
Relation of genetic risk factors to
environmental risk factors
• Gene-environment

Final Perspectives
• How genetic research related to SUDI does
help us
• Limitations
• Next steps
GENETIC RISK
FACTORS
26 Genes For Which Distribution of
polymorphisms Differs in SIDS*

Cardiac Channelopathies:
Serotonin (5-HT):
Autonomic Nervous System
Development
Infection & Inflammation:
EIGHT
SIX

Energy Production:
ONE



TOTAL
EIGHT
THREE
26
*Hunt CE, Hauck FR. SIDS: Gene-environment interactions, in Clinical Care
in Inherited Syndromes, ed. R Brugada, J Brugada, P Brugada. SpringerVerlag London Ltd. Guilford, UK, in press.
CARDIAC CHANNELOPATHIES (8)
(Arrhythmia Susceptibility Genes)

Long QT Syndrome (LQTS), SQTS
• Sodium channel (SCN5A)
• Sodium channel-interacting proteins



CAV3
SCN4B
GPD1-L
• Potassium channel (KCNQ1,KCNH2,
KCNE2)
• RyR2-encoded cardiac ryanodine
receptor (CPVT1)

Normal resting ECG
Genetic Risk Factors, cont.
Serotonin (5-HT) (3)


Important neurotransmitter
Polymorphisms in 3 genes:
• 5-HT transporter protein (5-HTT)
• Intron 2 of SLC6A4

VNTR polymorphism
• 5-HT FEV gene
Genetic Risk Factors, cont.
Autonomic Nervous System
Development (8)
• Paired-like homeobox 2A PHOX2A)
• PHOX2B
• Rearranged during transfection factor
(RET)
• Endothelin converting enzyme-1 (ECE1)
• T-cell leukemia homeobox (TLX3)
• Engrailed-1 (EN 1)
• Tyrosine hydroxylase (THO1)
• Monoamine oxidase A (MAOA)
Genetic Risk Factors, cont.
Infection & Inflammation (6)
(Activated Immune System)




Complement C4A (partial deletion)
Complement C4B (partial deletion)
Interleukin-10 (IL 10) (low levels)
IL-6*
• Mixed results, but multiple polymorphisms


VEGF* (Dashash M. Human Immunol 2006)
TNF-alpha (Ferrante L, et al. Human Immunol 2008)
*Increased levels in CSF in SIDS victims
DEFINITIONS

GENOTYPE
• Genetic make-up, with various
combinations of polymorphisms

PHENOTYPE
• Clinical manifestation of a genotype or
combined manifestation of several
different genotypes
• May not be evident on routine physical
examination or routine clinical testing
PHENOTYPES
Cardiac Channelopathies


Phenotype presumed, but not
confirmed
May be concealed (latent)* and
require provocation
• Sympathetic stress


Epinephrine infusion**
Sleep
• Acidosis
• Hypoxia
*Plant LD et al. JCI 2006; Tester DJ, et al. Heart Rhythm 2007
**Ackerman MJ. Heart Rhythm 2008
CARDIAC CHANNELOPATHIES
Screening

PRO
• Could theoretically “prevent” 5-10 % of
SIDS

CON (problems to overcome)
•
•
•
•
Cost of testing
Accuracy of interpretation
Frequency of false negative ECGs
Managing of false positive ECGs

May raise socioeconomic and psychosocial
problems
• Effectiveness and safety of treatment for
those positive with LQTS
Phenotypes, cont.
Serotonin (5-HT)


No matched phenotypes and
genotypes
Potential phenotypes
• Cardiorespiratory regulation

5-HTT knockout mice*: reduced ventilatory
response to CO2 (especially males)
• Other autonomic regulation
• Other…..?
Li A, Nattie E. J Physiol 2008
Phenotypes, cont.
Autonomic Nervous System Polymorphisms


No matched phenotypes/genotypes
Consistent with
• Clinical studies (limited) in young
infants later dying of SIDS
• Clinical studies in ALTE and preterm
infants
• Postmortem studies indicating
abnormalities in CNS areas involved
with autonomic and cardio-respiratory
regulation*
*Morley ME et al. Am J Med Genetics Part A. 2008
Phenotypes, cont.
Infection & Inflammation



No matched phenotypes/genotypes
Consistent with epidemiology studies
indicating increased frequency of
infections in SIDS infants
Identified polymorphisms:
• Gain-of-function in pro-inflammatory cytokines
• Loss-of-function in anti-inflammatory cytokines
GENE INTERACTIONS
Gene Interactions

Gene-environment
• “Genetics loads the gun and
environment pulls the trigger*”
• “Genes predispose, environment
disposes”
*Dr. Francis Collins, Past Director, National Human Genome
Research Institute, NIH
Environmental risk factors
Genetic risk factors
5-HTT
polymorphism
Smoking
ANS
polymorphism
Soft bedding
Impaired
autonomic
regulation
and arousal
Prone or side
sleeping
Prematurity
Hunt & Hauck, in press
Cardiac ion channel
polymorphism
Sudden
Infant
Death
Complement or
Interleukin
polymorphism
FUTURE DIRECTIONS
Research to Practice (Translation)

Antemortem phenotyping essential
• Screening
• Intervention

Broaden our focus to include other sudden
death groups
• Sudden Intrauterine Unexplained Death (SIUD)


1-2% of pregnancies end in stillbirth
Many shared features with SUDI and SIDS
• Sudden Unexplained Death in Childhood
(SUDC)

0.013 per 1 000 live births
• Sudden unexplained death in epilepsy
SUMMARY
The “Take Home” Message on Genetic Research

Provides biologic mechanisms for SUDI
when no “apparent” explanation at
autopsy
• Genetic autopsies not yet feasible



Especially important in those rare
occurrences of multiple SUDI in families
Helps to understand how environmental
risk factors may lead to SUDI in infants
genetically predisposed
MAJOR CHALLENGE:
• Not yet feasible to recognize in early infancy which
infants are genetically predisposed to SUDI if & when
confronted with relevant environmental risks
SUMMARY, cont.
The “Take Home” Message on Genetic Research

SUDI is a complex disorder
• No single cause
• Complex interactions between genetic and
environmental risk factor

No immediate help for families
• Highlights the importance of minimizing
environmental risk factors that are
modifiable

Expanding knowledge of genetic risk
factors will progressively lead to
improved understanding regarding
potential strategies for clinical testing
and (ultimately) intervention