Unexplained Death in Children, the Role of Genetics and Biobanking

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The Primary Ciliary Dyskinesia (PCD) Foundation, The Childrens Interstitial Lung Disease (chILD) Foundation and Genetic Diseases of Mucociliary Clearance Consortium (GDMCC) put together an interactive session for neonatologists, geneticists, pulmonologists, pathologists, pediatricians and other pediatric sub specialists to discuss the potential for biobanking genetic material in cases of unexplained or unexpected death in childhood that may be related to unidentified, rare or genetic disorders. These issues affect our PCD, ILD and Cystic Fibrosis patient communities, but clearly have broader implications for the rare and genetic disease communities at large. Why Biobanking? 1. Statistics change the game! Knowing what disease played a role can change the conversation about a genetic disease (i.e. newborn PCD case - Conor McGuire). 2. Biobanking can open many doors. Biobanking can unlock many doors to help families plan/get answers as well as improve our understanding of the individual and/or disease; thereby, changing the future (i.e. earlier treatment). 3. Family: Family planning; Closure for family Based on the input from this meeting and further discussions, our goal is to create a prototype in the near future that will serve as a national model.

Transcript of Unexplained Death in Children, the Role of Genetics and Biobanking

  • 1. Unexplained Death in Children,The Role of Genetics and Biobanking1 Copyright 2011 | PCD Foundation | Confidential

2. Agenda Welcome & Introductions Healthy Baby! to What Happened? in 31 Hours Conors PCD story: A mothers perspective How statistics change the conversation for genetic diseases Lessons Learned Conors PCD story: A medical perspective The role of genetics Current practices Biobanking: The Time is Right When, Where, How? How genetic insight may affect care & family planning Opportunities & challenges Potential impact on individual & overall disease state2 Copyright 2011 | PCD Foundation | Confidential 3. Introductions Stephanie Davis, MD Chief, Division of Pediatric Pulmonology, North Carolina ChildrensHospital GDMCC investigator Margaret Leigh, MD Director, Cystic Fibrosis Center, North Carolina Childrens Hospital GDMCC investigator Jon Popler, MD Pediatric Pulmonologist, Georgia Pediatric Pulmonology Associates chILD Foundation representative Carey Kauffman Conors mother PCD Foundation representative Mark R. Rigby, MD, PhD Biobanking insight and content, but not in attendance3 Copyright 2011 | PCD Foundation | Confidential 4. Healthy Baby! to What Happened? in 31 Hours Conor Nolan McGuire Full-term, 9lb 4 oz Healthy baby boy Congestion likely from quickdelivery leads to chest x-ray Situs Inversus 25% chance of Kartageners Communication Even if he has it, no need to worry until later in life. Donny Osmond has situs inversus - and hes just fine! Dont worry - hell just have a snottier nose than the other kids. All kids have snotty noses.4 Copyright 2011 | PCD Foundation | Confidential 5. Healthy Baby! to What Happened? in 31 Hours NICU Precautionary admission Planned to breast feed in AM Pronounced dead at 31 hours Lungs collapsed, heart shutdown, couldnt save him Never seen anything like it. I requested a test for PCD Response: Wouldnt be seenas a cause of death. A boxer who fights with onearm is bound to lose . . . Tested positive Hes not the first, nor the last Now, this statistic is onrecord for PCD . . . It changesthe conversation about PCD!5 Copyright 2011 | PCD Foundation | Confidential 6. Lessons Learned: A Medical PerspectiveRespiratory Failure as a Cause of Death in PCD Infant C.M. born at 39 weeks GA via spontaneous vaginaldelivery following uncomplicated pregnancy RR 88, but tachypnea resolved APGAR scores were 8 and 9 at 1 and 5 minutes 8 hours after delivery he was found to be grunting, withoxygen saturations of 80%6 Copyright 2011 | PCD Foundation | Confidential 7. Lessons Learned: A Medical PerspectiveRespiratory Failure as a Cause of Death in PCD Placed on oxygen; transferred to NICU Chest x-ray: situs inversus with well-expanded lungs and possible streaky perihilar infiltrates Echocardiogram revealed dextrocardia with normal cardiac function and vascular connections Desaturations to the high 80s For sepsis, IV ampicillin and gentamicin were initiated Hypoxia resolved and C.M. weaned to RA7 Copyright 2011 | PCD Foundation | Confidential 8. Lessons Learned: A Medical PerspectiveRespiratory Failure as a Cause of Death in PCD At 24 hours of age, C.M. had a sudden desaturation to 70% Intubated, placed on mechanical ventilation Hypoxia improved after pulmonary surfactant and fluid C.M. became pale, hypotensive, and developed progressive metabolic acidosis Placed on high frequency oscillatory ventilation Handbagging and chest compressions were initiated for HR < 80 5 doses of epinephrine, started on a dopamine infusion, but became increasingly pale and dusky, with only agonal heart rate Pronounced dead at 31 hours of life8 Copyright 2011 | PCD Foundation | Confidential 9. Autopsy Findings: First Report of Perinatal Death ofFull Term Infant with PCD11/29/11 9 9 Copyright 2011 | PCD Foundation | Confidential 10. Next StepsRespiratory Failure as a Cause of Death in PCDPCD specific: Further understanding of the mechanism causing respiratorydistress at birth is needed to help guide management of infantswith PCD Improved awareness of neonatal manifestations of PCD mayalso help to earlier identify children with this disease.Beyond PCD: Biobanking for all genetic disease to benefit Through biobanking, we will identify other infants and childrenwhere genetic diseases may have contributed to the cause ofdeath (i.e. pneumonia, SIDs, etc.) Lets get those statistics counted . . . And explore thepotential10 Copyright 2011 | PCD Foundation | Confidential 11. The Role of Genetics: Known PCD Genes in 2011GenesYear found ClassDNAI1 1999Outer Dynein Arms intermediate chainDNAH5 2002Outer Dynein Arms heavy chainDNAH112002Outer Dynein Arms heavy chainRPGR: 2003Several families with PCD+X-linked Retinitis PigmentosaOFD120061 family with PCD+X-linked Mental RetardationTXNDC32007Thioredoxin familyDNAI2 2008Outer Dynein Arms intermediate chainKTU / PF132008Cytoplasmic, pre-assembly of dynein armRSPH9 2009Radial Spoke HeadRSPH4A2009Radial Spoke HeadLRRC502009Cytoplasmic, pre-assembly of dynein armCCDC392011Dynein Regulatory ComplexCCDC402011Dynein Regulatory ComplexDNAL1 2011Outer Dynein Arms light chain11 Copyright 2011 | PCD Foundation | Confidential 12. Genes Known to Affect Motility of ChlamydomonasWith Human HomologsOuter Dynein ArmInner Dynein ArmKTUDNAH5DNAH9 DNAH9DNAH7 DNAH11 Hp28DNAI2 actin IC140IC140LRRC50ida9DNAI1 LC2/TCTE3 LC2/TCTE3Gas8/Gas11LC6Oda 13 LC6 DC3 Oda 14 DC3VFL2-Centrin VFL2-Centrin Oda 15 LC7 Fla 4 LC7LC8 LC8Radial spokeCentral pair RSPH9SPAG6SPAG6 RSPH4Ahpf20hpf20 12 (Modified from Porter and Sale 2000) Copyright 2011 | PCD Foundation | Confidential 13. PCD Genes: Dynein GenesDynein Genes DNAH5 DNAI1 absent/short ODA with slow, stiff DNAI2 and dyskinetic beat DNAL1TXNDC3: Some ODA absent/short with regions of slow, stiff and dyskinetic beatDNAH11: Normal EM with rapid beat and subtle limitation of cilia bending13 Copyright 2011 | PCD Foundation | Confidential 14. PCD Genes: Radial Spoke & Assembly Protein GenesRadial Spoke Genes RSPH9intermittent central pair loss and RSPH4A transpositions withcircular ciliary beatAssembly Protein Genes KTUabsent ODA and IDA with LRRC50 immotile ciliaCCDC39absent IDA and axonemalCCDC40disorganization with rigid, but fast, flicker beat14 Copyright 2011 | PCD Foundation | Confidential 15. Biobanking: The Time is RightWhen, Where, How & What? Review & discuss the logistics behind banking blood & tissueHow genetic insight may affect care & family planning Explosion of genetic informationOpportunities & challenges How do you approach a grieving family? Review the issues in creating a biobank & hurdles for consentPotential impact of biobanking Discuss how biobanking can help . . . Promote our understanding of the individual and the disease Change the conversation about genetic diseases15 Copyright 2011 | PCD Foundation | Confidential 16. When, Where, How and What?Moving Biobanking from strictly research arena to a clinical arena Previous Experiences: in vitro fertilization Harvested eggs are now frozen and stored for extended periods of time for a feeTo move from research to clinical.. Start with Education!16 Copyright 2011 | PCD Foundation | Confidential 17. When, Where, How and What?When? Unexpected admission to intensive care units Full term infant with no obvious etiology to respiratory distress Preterm infant with more severe BPD than expected Healthy infant admitted to PICU with RSV Healthy child admitted to PICU with ARDSFor todays discussion, lets focus on the Neonatal Intensive Care Unit (NICU)17 Copyright 2011 | PCD Foundation | Confidential 18. When, Where, How and What?When? At family conference weeks after baby dies Collect blood for DNA and other studies on all babies who die unexpectedly, store in temporary facility pending discussion At time of admission to NICU Discuss option to biobank blood and ask permission to do so if child should die At time of death Ask whether they want you to biobank blood for any immediate and/or future genetic testing (at time of autopsy discussion)18 Copyright 2011 | PCD Foundation | Confidential 19. When, Where, How and What?Where? Local institution Central biobankingHow? Standard operatingprocedures Trained personnel In rare disease,communication across sites19 Copyright 2011 | PCD Foundation | Confidential 20. When, Where, How and What?What Samples? Blood sample for lymphocyte transformation Most expensive Requires most blood and immediate technical support to dotransformation, but provides most DNA for testing Blood sample for DNA Intermediate amount of DNA May be used for several rounds of genetic testing Heel stick on filter paper (newborn screening) Easier storage Small amount of DNA Useful for very targeted testing20 Copyright 2011 | PCD Foundation | Confidential 21. Opportunities & ChallengesHow do you approach a grieving family? Simple and non-intrusive Educate family on importance Who should approach family? During illness or death, family likelyunable to understand importance ofblood or tissue collection21 Copyright 2011 | PCD Foundation | Confidential 22. Opportunities & ChallengesEstablishing a BiobankPhenotype is critical Must be able to collect appropriate medical history, past historyand family history from family or chart Unable to appropriately analyze blood tissue unless phenotypeunderstoodMany hospitals do not have facilities to freeze specimens Shipping to a central facility requires specialized packaging22 Copyright 2011 | PCD Foundation | Confidential 23. Opportunities & ChallengesEstablishing a BiobankStandard operating proceduresRegulatory issues Informed consent and IRBs; Should allow collection of clinicaldata and sharing across sites Consistency across sitesWho orders genetic testing on the samples? Neonatologists, geneticist, pediatric specialist, primarypediatrician? Who pays for this type of project?Interpretation of genetic testing