Prenatal diagnosis for Joubert Prenatal diagnosis for Joubert syndrome:syndrome:

Challenges and PossibilitiesChallenges and Possibilities

Ian A. Glass, MB ChB, MD, FACMGIan A. Glass, MB ChB, MD, FACMG

Associate Professor of Pediatrics and MedicineAssociate Professor of Pediatrics and Medicine

Prenatal Diagnosis (PND)Prenatal Diagnosis (PND)Topics for this seminarTopics for this seminar

• Goals of PND in generalGoals of PND in general

• Methods of PNDMethods of PND

• PND in Joubert syndromePND in Joubert syndrome

• Strengths/weaknesses of PND for JSStrengths/weaknesses of PND for JS

• Future directions for PND of JSFuture directions for PND of JS

Goals of PNDGoals of PND• Facilitate informed reproductive choices Facilitate informed reproductive choices

• Reduce anxiety in high-risk groupsReduce anxiety in high-risk groups

• Enable prenatal treatment, if availableEnable prenatal treatment, if available

• Ensure the birth of unaffected infantsEnsure the birth of unaffected infants

(termination of affected fetus)(termination of affected fetus)

• Enable preparations for the birth of an Enable preparations for the birth of an affected child affected child

• Medical careMedical care

• Psychological preparationsPsychological preparations

Indications for PNDIndications for PND• Screening of high risk groupsScreening of high risk groups

• Advanced Maternal Age (AMA)Advanced Maternal Age (AMA)• Particular ethnic groupsParticular ethnic groups

• Cystic fibrosis in CaucasiansCystic fibrosis in Caucasians• Sickle cell anemia in African-AmericansSickle cell anemia in African-Americans

• Specific prenatal testingSpecific prenatal testing• Family history of prior affected childFamily history of prior affected child

• Muscular dystrophyMuscular dystrophy• Joubert syndromeJoubert syndrome

Reproductive options for couples Reproductive options for couples who have a child with JSwho have a child with JS

• Accept the risk without PNDAccept the risk without PND

• Accept the risk and consider PND imaging:Accept the risk and consider PND imaging:– To be prepared for an affected childTo be prepared for an affected child– To terminate an affected fetusTo terminate an affected fetus

• Sperm or egg donor to reduce riskSperm or egg donor to reduce risk

• Choose to adoptChoose to adopt

• Choose not to have additional childrenChoose not to have additional children

ALL of these choices are valid!

Methods of PNDMethods of PND• Non-invasive testingNon-invasive testing

• serum markers serum markers • imaging by ultrasound, fetal-MRIimaging by ultrasound, fetal-MRI

• Invasive testingInvasive testing• amniocentesisamniocentesis• chorionic villus sampling (CVS)chorionic villus sampling (CVS)

Non-invasive testing: ImagingNon-invasive testing: Imaging

• Ultrasound (US)Ultrasound (US)• Fetal MRIFetal MRI• Screening for high risk groups (e.g. AMA)Screening for high risk groups (e.g. AMA)• Directed diagnostic imaging for:Directed diagnostic imaging for:

• Fetuses with abnormalitiesFetuses with abnormalities• Family history of birth defectFamily history of birth defect

• Post-natal correlations to confirm PND predictionPost-natal correlations to confirm PND prediction• Postnatal follow-up exam and/or testingPostnatal follow-up exam and/or testing• Fetal autopsy if demise or terminationFetal autopsy if demise or termination

Correlations often not performed !!!Correlations often not performed !!!

Normal Fetal Hand:Normal Fetal Hand:3D US3D US

Polydactyly:Polydactyly:3D US3D US

Normal Face:Normal Face:2D and 3D US2D and 3D US

Non-invasive testing: Imaging

Prenatal Hydrocephalus on US

Imaging: Post-natal correlation

Hydrocephalus on MRI after birth

Invasive testing: AmniocentesisInvasive testing: Amniocentesis

Test Risk of Loss Timing Result• Amniocentesis 1/200 16 wk 18-22wk

Invasive testing: Chorionic villus samplingInvasive testing: Chorionic villus sampling

Test Risk of Loss Timing Result• CVS 1/100 11 wk 11-12wk

PND in Joubert syndromePND in Joubert syndrome

The flow of genetic information: The flow of genetic information: Chromosomes Chromosomes Genes (DNA) Genes (DNA) Message (RNA) Message (RNA)

ProteinProtein

CellCellNucleusNucleus

ChromosomesChromosomes

Gene made of DNA

ProteinProtein

RNA

Testing Opportunities

Family with a child with JSFamily with a child with JS

Diagnosis: JS+ MTS

?RR = 25%What prenatal testing is available?

Methods for PND in JSMethods for PND in JS

• Invasive testingInvasive testing Useful for JS?Useful for JS?• amniocentesisamniocentesis Maybe Maybe**

• chorionic villus sampling (CVS)chorionic villus sampling (CVS) Maybe*Maybe*

• Non-invasive testingNon-invasive testing• serum markers (triple screen, AFP)serum markers (triple screen, AFP) NoNo

• imaging by ultrasound, fetal-MRIimaging by ultrasound, fetal-MRI YESYES

Most of these methods are not useful because chromosomal, DNA* Most of these methods are not useful because chromosomal, DNA*

and protein markers for JS are not availableand protein markers for JS are not available

*If a known mutation in a JS gene

Is DNA testing currently available for JS?Is DNA testing currently available for JS?

• Best situation: one gene causes all JS casesBest situation: one gene causes all JS cases–But we have at least 5 JS genes known/mapped But we have at least 5 JS genes known/mapped alreadyalready

• Goal: direct DNA testing once JS genes are knownGoal: direct DNA testing once JS genes are known• 2006: Only two direct DNA tests are clinically 2006: Only two direct DNA tests are clinically “available” for JS for the “available” for JS for the NPHP1 NPHP1 and and AHI1 AHI1 genes,genes, accounting for <15% of JSaccounting for <15% of JS• Specific Specific genegene testing may be indicated if an older testing may be indicated if an older sibling has a mutation in a known JS genesibling has a mutation in a known JS gene

What is available now?What is available now?

• Prenatal imaging by ultrasound scanning Prenatal imaging by ultrasound scanning (considerable experience)(considerable experience)

• Prenatal imaging by fetal MRI scanning Prenatal imaging by fetal MRI scanning (increasing experience)(increasing experience)

PND of JSPND of JSFamily History is KeyFamily History is Key

CharacteristicCharacteristic PostnatalPostnatal PrenatalPrenatalMTSMTS ++ ??Small vermis /large cisterna Small vermis /large cisterna magnamagna

++ +/-+/-

HypotoniaHypotonia ++ --AtaxiaAtaxia ++ --Abnormal Eye MovementsAbnormal Eye Movements ++ --Developmental DelayDevelopmental Delay ++ --Irregular breathing patternIrregular breathing pattern ++ +/-+/-PolydactylyPolydactyly ++ ++EncephaloceleEncephalocele ++ ++Abnormal kidneysAbnormal kidneys ++ +/-+/-

Molar Tooth Sign Molar Tooth Sign

deep interpeduncular fossa

thick, elongated SCPs

cerebellar vermis hypoplasia

Cerebellar vermis in uteroCerebellar vermis in utero

Normal HypoplasticNormal

JS in utero: JS in utero: absence of cerebellar vermisabsence of cerebellar vermis

UltrasoundUltrasound MRIMRI

JS: enlarged cisterna magnaJS: enlarged cisterna magna

UltrasoundUltrasound MRIMRI

JS in utero:JS in utero:polydactylypolydactyly

123

4

5

6

Aslan et al. 2002

JS in utero:JS in utero:encephaloceleencephalocele

Wang et al. 1999

US for PND: promise and perilsUS for PND: promise and perils• Advantages:Advantages:

– Non-invasiveNon-invasive– Can see important structures: brain, fingers, kidneysCan see important structures: brain, fingers, kidneys– Can be repeated throughout pregnancyCan be repeated throughout pregnancy– Relatively inexpensiveRelatively inexpensive– Standardized measurementsStandardized measurements

• Disadvantages:Disadvantages:– Technician-dependent: angle of transducerTechnician-dependent: angle of transducer

– Observer-dependent: experience in looking at brainObserver-dependent: experience in looking at brain

– May not see subtle abnormalities May not see subtle abnormalities

– Timing is crucial: defects may not be visible earlyTiming is crucial: defects may not be visible early

For couples who desire prenatal imagingFor couples who desire prenatal imaging

• 11-12 wks: baseline US for dates, nuchal fold11-12 wks: baseline US for dates, nuchal fold• 16 wks: US for cranial views, skull, fingers, kidney16 wks: US for cranial views, skull, fingers, kidney• 18 wks: US to confirm cerebellar growth18 wks: US to confirm cerebellar growth• 20-22 wks: US for above + fetal MRI20-22 wks: US for above + fetal MRI• Further imaging, dependent on prior findingsFurther imaging, dependent on prior findings• If possible, review by an experienced radiologist, or If possible, review by an experienced radiologist, or

perinatologist in evaluations of the posterior fossaperinatologist in evaluations of the posterior fossa

Improving PND of JSImproving PND of JS• Systematic review of prenatal imaging Systematic review of prenatal imaging • Correlation with outcomesCorrelation with outcomes• Follow ongoing pregnancies with imaging studiesFollow ongoing pregnancies with imaging studies

• HypothesisHypothesis: Systematic review of ultrasound and/or : Systematic review of ultrasound and/or fetal MRI imaging will improve diagnosis of JS and fetal MRI imaging will improve diagnosis of JS and generate guidelines for prenatal monitoring of at-risk generate guidelines for prenatal monitoring of at-risk pregnanciespregnancies

JS PND SummaryJS PND Summary

• Can we diagnose JS prenatally given a prior Can we diagnose JS prenatally given a prior family history?family history?– Sometimes, but the reliability is unknownSometimes, but the reliability is unknown

• Can we diagnose JS prenatally without a prior Can we diagnose JS prenatally without a prior family history?family history?– Almost never, if at allAlmost never, if at all

• Improved PND is needed, imaging is our best Improved PND is needed, imaging is our best option at this timeoption at this time

Making an informed choiceMaking an informed choice

• A Genetic Counselor or Geneticist can helpA Genetic Counselor or Geneticist can help– Discuss optionsDiscuss options– Provide resources and support Provide resources and support

• When possible, get information prior to When possible, get information prior to getting pregnant (preconception counseling)getting pregnant (preconception counseling)

• www.genetests.orgwww.genetests.org or or www.nsgc.orgwww.nsgc.org for a for a list of local genetic counselorslist of local genetic counselors

Current Research EffortsCurrent Research Efforts

• Linkage and other methods to locate new Linkage and other methods to locate new genesgenes

• Structural and functional MRI imagingStructural and functional MRI imaging

• Improved clinical understanding (JSF Improved clinical understanding (JSF Registry, Biobank)Registry, Biobank)

• Accurate prenatal diagnosisAccurate prenatal diagnosis

• Recommendations for medical managementRecommendations for medical management

How to participate in Joubert How to participate in Joubert researchresearch

• Contact us:Contact us:– Dana Knutzen, MS, GC and Melissa Parisi, MD, PhDDana Knutzen, MS, GC and Melissa Parisi, MD, PhD

kknutzd@u.washington.edunutzd@u.washington.edumparisi@u.washington.edumparisi@u.washington.edu800-246-6312, 206-987-3832800-246-6312, 206-987-3832

– Ian A. Glass, MD and Dan Doherty, MD, PhDIan A. Glass, MD and Dan Doherty, MD, PhDian.glass@seattlechildrens.orgian.glass@seattlechildrens.orgdan.doherty@seattlechildrens.orgdan.doherty@seattlechildrens.org206-987-5142206-987-5142206-987-2489206-987-2489

AcknowledgmentsAcknowledgmentsUW Joubert CenterUW Joubert Center

• Phillip Chance, MDPhillip Chance, MD

• Jon Adkins, BS Jon Adkins, BS

• Craig Bennett, PhDCraig Bennett, PhD

• Daniel Doherty, MD, PhDDaniel Doherty, MD, PhD

• Ian Glass, MDIan Glass, MD

• Nick Gorden, BSNick Gorden, BS

• Dana Knutzen, MSDana Knutzen, MS

Research CollaboratorsResearch Collaborators• William Dobyns, MDWilliam Dobyns, MD• Joseph Gleeson, MDJoseph Gleeson, MD• Friedhelm Hildebrandt, MDFriedhelm Hildebrandt, MD• Bernard Maria, MDBernard Maria, MD• David Nyberg, MDDavid Nyberg, MD• Hamit Ozyurek, MDHamit Ozyurek, MD• Joseph Pinter, MDJoseph Pinter, MD• Dennis Shaw, MDDennis Shaw, MD• Other collaborators!Other collaborators!

You! Children with JSRD and their Families You! Children with JSRD and their Families JSF & RCDJSF & RCD