Unexplained Death in Children,The Role of Genetics and Biobanking1                          © Copyright 2011 | PCD Foundat...
Agenda•       Welcome & Introductions•       “Healthy Baby!” to “What Happened?” in 31 Hours         – Conor’s PCD story: ...
Introductions•       Stephanie Davis, MD        – Chief, Division of Pediatric Pulmonology, North Carolina Children’s     ...
“Healthy Baby!” to “What Happened?” in 31 Hours•       Conor Nolan McGuire         – Full-term, 9lb 4 oz         – “Health...
“Healthy Baby!” to “What Happened?” in 31 Hours•       NICU        – Precautionary admission        – Planned to breast fe...
Lessons Learned: A Medical PerspectiveRespiratory Failure as a Cause of Death in PCD•       Infant C.M. born at 39 weeks G...
Lessons Learned: A Medical PerspectiveRespiratory Failure as a Cause of Death in PCD•       Placed on oxygen; transferred ...
Lessons Learned: A Medical PerspectiveRespiratory Failure as a Cause of Death in PCD•       At 24 hours of age, C.M. had a...
Autopsy Findings: First Report of Perinatal Death ofFull Term Infant with PCD11/29/11                                     ...
Next StepsRespiratory Failure as a Cause of Death in PCD•        PCD specific:          – Further understanding of the mec...
The Role of Genetics: Known PCD Genes in 2011Genes        Year found   ClassDNAI1           1999      Outer Dynein Arms in...
Genes Known to Affect Motility of ChlamydomonasWith Human Homologs                            Outer Dynein Arm            ...
PCD Genes: Dynein GenesDynein Genes• DNAH5• DNAI1                               absent/short ODA with slow, stiff• DNAI2  ...
PCD Genes: Radial Spoke & Assembly Protein GenesRadial Spoke Genes• RSPH9          intermittent central                   ...
Biobanking: The Time is Right•        When, Where, How & What?          – Review & discuss the logistics behind banking bl...
When, Where, How and What?•        Moving Biobanking from strictly research arena to a clinical         arena          • P...
When, Where, How and What?•        When?         – Unexpected admission to intensive care units            • Full term inf...
When, Where, How and What?•        When?         • At family conference weeks after baby dies            • Collect blood f...
When, Where, How and What?•        Where?          – Local institution          – Central biobanking•        How?         ...
When, Where, How and What?•        What Samples?         – Blood sample for lymphocyte transformation            • Most ex...
Opportunities & Challenges•        How do you approach a grieving family?          – Simple and non-intrusive          – E...
Opportunities & ChallengesEstablishing a Biobank•        Phenotype is critical          – Must be able to collect appropri...
Opportunities & ChallengesEstablishing a Biobank•        Standard operating procedures•        Regulatory issues          ...
Potential Impact of Biobanking•        Statistics change the game!          • Knowing what disease played a role can chang...
Neonatology Associates of AtlantaThank You!   Ken Kupke, MD & Susie Edelman                                            Car...
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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.

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Unexplained Death in Children, the Role of Genetics and Biobanking

  1. 1. Unexplained Death in Children,The Role of Genetics and Biobanking1 © Copyright 2011 | PCD Foundation | Confidential
  2. 2. Agenda• Welcome & Introductions• “Healthy Baby!” to “What Happened?” in 31 Hours – Conor’s PCD story: A mother’s perspective – How statistics ‘change the conversation’ for genetic diseases• Lessons Learned – Conor’s 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 state 2 © Copyright 2011 | PCD Foundation | Confidential
  3. 3. Introductions• Stephanie Davis, MD – Chief, Division of Pediatric Pulmonology, North Carolina Children’s Hospital – GDMCC investigator• Margaret Leigh, MD – Director, Cystic Fibrosis Center, North Carolina Children’s Hospital – GDMCC investigator• Jon Popler, MD – Pediatric Pulmonologist, Georgia Pediatric Pulmonology Associates – chILD Foundation representative• Carey Kauffman – Conor’s mother – PCD Foundation representative• Mark R. Rigby, MD, PhD – Biobanking insight and content, but not in attendance 3 © Copyright 2011 | PCD Foundation | Confidential
  4. 4. “Healthy Baby!” to “What Happened?” in 31 Hours• Conor Nolan McGuire – Full-term, 9lb 4 oz – “Healthy” baby boy• Congestion likely from “quick delivery” leads to chest x-ray – Situs Inversus – 25% chance of Kartagener’s• Communication – “Even if he has it, no need to worry until later in life.” – “Donny Osmond has situs inversus - and he’s just fine!” – “Don’t worry - he’ll just have a snottier nose than the other kids. All kids have snotty noses.” 4 © Copyright 2011 | PCD Foundation | Confidential
  5. 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 shut down, couldn’t save him – “Never seen anything like it.”• I requested a test for PCD – Response: “Wouldn’t be seen as a cause of death.” – A boxer who fights with one arm is bound to lose . . .• Tested positive – He’s not the first, nor the last – Now, this statistic is ‘on record’ for PCD . . . It changes the conversation about PCD! 5 © Copyright 2011 | PCD Foundation | Confidential
  6. 6. Lessons Learned: A Medical PerspectiveRespiratory Failure as a Cause of Death in PCD• Infant C.M. born at 39 weeks GA via spontaneous vaginal delivery 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, with oxygen saturations of 80% 6 © Copyright 2011 | PCD Foundation | Confidential
  7. 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 80’s – For sepsis, IV ampicillin and gentamicin were initiated – Hypoxia resolved and C.M. weaned to RA 7 © Copyright 2011 | PCD Foundation | Confidential
  8. 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 life 8 © Copyright 2011 | PCD Foundation | Confidential
  9. 9. Autopsy Findings: First Report of Perinatal Death ofFull Term Infant with PCD11/29/11 9 9 © Copyright 2011 | PCD Foundation | Confidential
  10. 10. Next StepsRespiratory Failure as a Cause of Death in PCD• PCD specific: – Further understanding of the mechanism causing respiratory distress at birth is needed to help guide management of infants with PCD – Improved awareness of neonatal manifestations of PCD may also 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 children where genetic diseases may have contributed to the cause of death (i.e. pneumonia, SIDs, etc.) – Let’s get those statistics counted . . . And explore the potential 10 © Copyright 2011 | PCD Foundation | Confidential
  11. 11. The Role of Genetics: Known PCD Genes in 2011Genes Year found ClassDNAI1 1999 Outer Dynein Arms intermediate chainDNAH5 2002 Outer Dynein Arms heavy chainDNAH11 2002 Outer Dynein Arms heavy chainRPGR: 2003 Several families with PCD+X-linked Retinitis PigmentosaOFD1 2006 1 family with PCD+X-linked Mental RetardationTXNDC3 2007 Thioredoxin familyDNAI2 2008 Outer Dynein Arms intermediate chainKTU / PF13 2008 Cytoplasmic, pre-assembly of dynein armRSPH9 2009 Radial Spoke HeadRSPH4A 2009 Radial Spoke HeadLRRC50 2009 Cytoplasmic, pre-assembly of dynein armCCDC39 2011 Dynein Regulatory ComplexCCDC40 2011 Dynein Regulatory ComplexDNAL1 2011 Outer Dynein Arms light chain 11 © Copyright 2011 | PCD Foundation | Confidential
  12. 12. Genes Known to Affect Motility of ChlamydomonasWith Human Homologs Outer Dynein Arm Inner Dynein Arm KTU DNAH5DNAH9 DNAH9 DNAH7 DNAH11 Hp28 DNAI2 actin IC140 IC140 LRRC50 ida9 DNAI1 LC2/TCTE3 LC2/TCTE3 Gas8/Gas11 LC6 Oda 13 LC6 DC3 Oda 14 DC3 VFL2-Centrin VFL2-Centrin Oda 15 LC7 Fla 4 LC7 LC8 LC8 Radial spokeCentral pair RSPH9 SPAG6 SPAG6 RSPH4A hpf20 hpf20 12 (Modified from Porter and Sale 2000) © Copyright 2011 | PCD Foundation | Confidential
  13. 13. PCD Genes: Dynein GenesDynein Genes• DNAH5• DNAI1 absent/short ODA with slow, stiff• DNAI2 and dyskinetic beat• DNAL1• TXNDC3: Some ODA absent/short with regions of slow, stiff and dyskinetic beat• DNAH11: Normal EM with rapid beat and subtle limitation of cilia bending 13 © Copyright 2011 | PCD Foundation | Confidential
  14. 14. PCD Genes: Radial Spoke & Assembly Protein GenesRadial Spoke Genes• RSPH9 intermittent central pair loss and• RSPH4A transpositions with circular ciliary beatAssembly Protein Genes• KTU absent ODA and IDA with• LRRC50 immotile cilia• CCDC39 absent IDA and axonemal• CCDC40 disorganization with rigid, but fast, flicker beat 14 © Copyright 2011 | PCD Foundation | Confidential
  15. 15. Biobanking: The Time is Right• When, Where, How & What? – Review & discuss the logistics behind banking blood & tissue• How genetic insight may affect care & family planning – Explosion of genetic information• Opportunities & challenges – How do you approach a grieving family? – Review the issues in creating a biobank & hurdles for consent• Potential impact of biobanking – Discuss how biobanking can help . . . • Promote our understanding of the individual and the disease • Change the conversation about genetic diseases 15 © Copyright 2011 | PCD Foundation | Confidential
  16. 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 fee• To move from research to clinical.. • Start with Education! 16 © Copyright 2011 | PCD Foundation | Confidential
  17. 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 ARDS For today’s discussion, let’s focus on the Neonatal Intensive Care Unit (NICU) 17 © Copyright 2011 | PCD Foundation | Confidential
  18. 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. 19. When, Where, How and What?• Where? – Local institution – Central biobanking• How? – Standard operating procedures – Trained personnel – In rare disease, communication across sites 19 © Copyright 2011 | PCD Foundation | Confidential
  20. 20. When, Where, How and What?• What Samples? – Blood sample for lymphocyte transformation • Most expensive • Requires most blood and immediate technical support to do transformation, 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 testing 20 © Copyright 2011 | PCD Foundation | Confidential
  21. 21. Opportunities & Challenges• How do you approach a grieving family? – Simple and non-intrusive – Educate family on importance – Who should approach family? – During illness or death, family likely unable to understand importance of blood or tissue collection 21 © Copyright 2011 | PCD Foundation | Confidential
  22. 22. Opportunities & ChallengesEstablishing a Biobank• Phenotype is critical – Must be able to collect appropriate medical history, past history and family history from family or chart – Unable to appropriately analyze blood tissue unless phenotype understood• Many hospitals do not have facilities to freeze specimens – Shipping to a central facility requires specialized packaging 22 © Copyright 2011 | PCD Foundation | Confidential
  23. 23. Opportunities & ChallengesEstablishing a Biobank• Standard operating procedures• Regulatory issues – Informed consent and IRBs; Should allow collection of clinical data and sharing across sites – Consistency across sites• Who orders genetic testing on the samples? – Neonatologists, geneticist, pediatric specialist, primary pediatrician? – Who pays for this type of project?• Interpretation of genetic testing for family: – Ordering physician and/or genetic counselor 23 © Copyright 2011 | PCD Foundation | Confidential
  24. 24. Potential Impact of Biobanking• Statistics change the game! • Knowing what disease played a role can change the conversation about a genetic disease (i.e. PCD).• Biobanking can open many doors. • Biobanking can unlock many doors to help family’s plan/get answers • Improve our understanding of individual and/or disease; thereby, change the future. (i.e. earlier treatment)• Family • Family planning • Closure for family 24 © Copyright 2011 | PCD Foundation | Confidential
  25. 25. Neonatology Associates of AtlantaThank You! Ken Kupke, MD & Susie Edelman Carey Kauffman To Learn More or t 404.840.7151 Get Involved: e ckauffman@pcdfoundation.org Stephanie Davis, MD e stephanie_davis@med.unc.edu Margaret Leigh, MD e margaret_leigh@med.unc.edu PCD Foundation pcdfoundation.org chILD Foundation childfoundation.org25 © Copyright 2011 | PCD Foundation | Confidential

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