Prenatal diagnosis (PND) in Joubert syndrome Dan Doherty, MD/PhD

Goals of PND Provide reassurance/reduce uncertainty Prepare for the birth of an affected child – Delivery route – Delivery location – Emotional preparation Assure the birth of an unaffected child – Pregnancy termination – (Preimplantation genetic diagnosis) Allow for prenatal treatment

JS is autosomal recessive* Recurrence risk = 25%

Reproductive options Accept the risk without PND

Reproductive options Accept the risk without PND Accept the risk and consider PND: – To prepare for an affected child – To terminate an affected pregnancy

Reproductive options Accept the risk without PND Accept the risk and consider PND: – To prepare for an affected child – To terminate an affected pregnancy Sperm or egg donor to reduce risk

Reproductive options Accept the risk without PND Accept the risk and consider PND: – To prepare for an affected child – To terminate an affected pregnancy Sperm or egg donor to reduce risk Choose to adopt

Reproductive options Accept the risk without PND Accept the risk and consider PND: – To prepare for an affected child – To terminate an affected pregnancy Sperm or egg donor to reduce risk Choose to adopt Choose not to have additional children

Reproductive options Accept the risk without PND Accept the risk and consider PND: – To prepare for an affected child – To terminate an affected pregnancy Sperm or egg donor to reduce risk Choose to adopt Choose not to have additional children ALL of these choices are valid.

Risk scenarios Prior affected child: 25% risk each pregnancy – Clinical diagnosis only -> prenatal imaging – Clinical and genetic diagnosis -> genetic testing and prenatal imaging No family history: population risk (very low) – Routine prenatal care Population risk of birth defects 2-3%

Testing Strategies Available – Prenatal imaging – Fetal DNA testing Not Available – Maternal serum screening – Biochemical testing (amniotic fluid)

Imaging diagnosis Consistent finding – Cerebellar vermis hypoplasia Molar tooth sign not seen before 24 weeks Supportive findings (rare) – Polydactyly – Cystic kidneys – Encephalocele – Increased respiratory rate

Vermis hypoplasia US Superior vermis intact Inferior vermis absent

Vermis hypoplasia fetal MRI 21 wks Affected 22 wks Unaffected

Molar tooth sign in utero 29 wks gestationPost-natal

Polydactyly in utero Aslan et al. 2002

Encephalocele in utero Fetal MRI (JS)US (not JS)

Specific imaging strategy Usual prenatal care and screening Consultation with a tertiary care center week US 20 week US week fetal MRI adapted from Doherty et al We are happy to consult with OB providers/radiologists about imaging diagnosis. We prefer to be involved starting before/early in the pregnancy.

Imaging diagnosis Advantages: – Non-invasive – Can visualize brain, fingers, kidneys – Can be repeated throughout pregnancy – Relatively inexpensive Disadvantages: – Technician-dependent – Radiologist-dependent – May not see subtle abnormalities – Late diagnosis

Background: Genetic Testing Gene Estimated frequency NPHP1 ~2% AHI1 ~10% CEP290 ~10% RPGRIP1L ~5% MKS3 ~10% ARL13B <1% CC2D2A ~10% INPP5E ? OFD1 <1% TOTAL <50% Frequency of mutations in patients with JS

DNA testing strategy Test affected child prior to next pregnancy

DNA testing strategy Test affected child prior to next pregnancy

DNA testing strategy Test affected child prior to next pregnancy No mutation identified -> PND by imaging

DNA testing strategy Test affected child prior to pregnancy No mutation identified -> PND by imaging Mutation identified – Preimplantation genetic diagnosis – Chorionic villous sampling – Amniocentesis

DNA collection techniques early placental tissue 10-12wk gestation Risks: – Miscarriage (1/100) – Infection Less available in US DNA dx wks Chorionic villus sampling

DNA collection techniques Amniocentesis fetal skin cells in fluid >15 wk gestation Risks: – Miscarriage (1/500) – Infection – Fluid leak – Fetal injury DNA dx ~20+ wks

Making a Decision Genetic Counselor or Geneticist can help – Discuss options – Provide resources and support Consider contacting them before pregnancy or early in pregnancy See for a list of local GC’s

Family history of JS – Known mutation -> PND by gene testing – No mutation -> PND by prenatal US & fetal MRI No family history – JS not distinguishable from other cerebellar vermis hypoplasias before 24wks – Variable features can facilitate diagnosis Encephalocele, polydactyly, cystic kidneys After 27wks, dx possible by imaging alone Conclusions

Acknowledgements University of Washington Joubert Center Dana Knutzen, Genetic Counselor