Unexplained Death in Children, the Role of Genetics and Biobanking

1© Copyright 2011 | PCD Foundation | Confidential

Unexplained Death in Children,The Role of Genetics and Biobanking

© Copyright 2011 | PCD Foundation | Confidential2

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


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


“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 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 otherkids. All kids have snottynoses.”


“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 changesthe conversation about PCD!


Lessons Learned: A Medical Perspective

Respiratory 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, with

oxygen saturations of 80%




• 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




• 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 heartrate

– Pronounced dead at 31 hours of life

© Copyright 2011 | PCD Foundation | Confidential911/29/11 9

Autopsy Findings: First Report of Perinatal Death ofFull Term Infant with PCD


Next Steps


• PCD specific:– Further understanding of the mechanism causing respiratory

distress 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 children

where genetic diseases may have contributed to the cause ofdeath (i.e. pneumonia, SIDs, etc.)

– Let’s get those statistics counted . . . And explore thepotential


The Role of Genetics: Known PCD Genes in 2011

Genes Year found Class

DNAI1 1999 Outer Dynein Arms intermediate chain

DNAH5 2002 Outer Dynein Arms heavy chain

DNAH11 2002 Outer Dynein Arms heavy chain

RPGR: 2003 Several families with PCD+X-linked Retinitis Pigmentosa

OFD1 2006 1 family with PCD+X-linked Mental Retardation

TXNDC3 2007 Thioredoxin family

DNAI2 2008 Outer Dynein Arms intermediate chain

KTU / PF13 2008 Cytoplasmic, pre-assembly of dynein arm

RSPH9 2009 Radial Spoke Head

RSPH4A 2009 Radial Spoke Head

LRRC50 2009 Cytoplasmic, pre-assembly of dynein arm

CCDC39 2011 Dynein Regulatory Complex

CCDC40 2011 Dynein Regulatory Complex

DNAL1 2011 Outer Dynein Arms light chain


Oda 13Oda 14Oda 15Fla 4

DNAH7

Hp28actinIC140

ida9

DNAH9

VFL2-Centrin

SPAG6

LC8

Gas8/Gas11

hpf20

Outer Dynein Arm Inner Dynein Arm

(Modified from Porter and Sale 2000)

Radial spokeCentral pair RSPH9RSPH9

RSPH4ARSPH4A

LC7DC3LC6

LC2/TCTE3

Genes Known to Affect Motility of ChlamydomonasWith Human Homologs

DNAI2DNAI2

DNAH9DNAH5DNAH5

DNAI1DNAI1

SPAG6

LC8

hpf20

DNAH11DNAH11

KTUKTU

LC7DC3LC6

LC2/TCTE3

LRRC50LRRC50

Hp28

IC140

VFL2-Centrin


Dynein Genes• DNAH5• DNAI1• DNAI2• DNAL1

• TXNDC3: Some ODA absent/short with regions of slow, stiffand dyskinetic beat

• DNAH11: Normal EM with rapid beat and subtle limitation ofcilia bending

PCD Genes: Dynein Genes

absent/short ODA with slow, stiffand dyskinetic beat


Radial Spoke Genes• RSPH9• RSPH4A

Assembly Protein Genes• KTU• LRRC50

• CCDC39• CCDC40

intermittent central pair loss andtranspositions with circular ciliary beat

absent ODA and IDA withimmotile cilia

absent IDA and axonemaldisorganization with rigid, but fast,flicker beat

PCD Genes: Radial Spoke & Assembly Protein Genes


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


When, Where, How and What?

• Moving Biobanking from strictly research arena to a clinicalarena• 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!



• 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 theNeonatal Intensive Care Unit (NICU)



• When?• At family conference weeks after baby dies

• Collect blood for DNA and other studies on all babies who dieunexpectedly, 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 immediateand/or future genetic testing (at time of autopsy discussion)



• Where?– Local institution– Central biobanking

• How?– Standard operating

procedures– Trained personnel– In rare disease,

communication across sites



• 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


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 ofblood or tissue collection



• 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

Establishing a Biobank



• Standard operating procedures• Regulatory issues

– Informed consent and IRBs; Should allow collection of clinicaldata and sharing across sites

– Consistency across sites• Who orders genetic testing on the samples?

– Neonatologists, geneticist, pediatric specialist, primarypediatrician?

– Who pays for this type of project?• Interpretation of genetic testing for family:

– Ordering physician and/or genetic counselor

Establishing a Biobank


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


Thank You!

Carey Kauffmant 404.840.7151e [email protected]

Stephanie Davis, MDe [email protected]

PCD Foundationpcdfoundation.org

chILD Foundationchildfoundation.org

To Learn More orGet Involved:

Margaret Leigh, MDe [email protected]

Neonatology Associates of AtlantaKen Kupke, MD & Susie Edelman

Unexplained Death in Children, the Role of Genetics and Biobanking

Health & Medicine

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