Genetic testing for CFMF

1. Genetic Diagnostic Approach
to the Malformed Fetus
Sara Hisham El-Dessouky
Associate Professor of Human Genetics & Fetal Medicine
Head of Prenatal Diagnosis & Fetal Medicine Department
National Research Centre

2. Obstetricians & Gynecologists as Primary Genetic Counselors

4. Multidisciplinary Approach
DIAGNOSIS
maternal-Fetal
medicine Sonographer
Prenatal care
provider
Geneticist
Obstetrician &
Gynecologist
MANAGEMENT
Prenatal care provider
Neonatologist
Pediatric geneticist

5. Just because it’s congenital
it doesn’t mean it’s genetic

6. Causes of birth defects

7. Windows of vulnerability
critical periods of development during gestation

9. • obstetric history
• screening results
• results of any invasive procedures
• review records of previous affected children.
• Family history
History
• Single anomaly
• Multiple anomalies
• Photos
Examination
• Chromosome analysis
• Metabolic analysis
• Molecular analysis
• Fetal MRI
• Radiographs after delivery, Autopsy
Investigations
• Use of databases, search engines, books,
• published literature
Making the
diagnosis
The process of making diagnosis:

10. History taking
Parental
ages at
conception
Method of
Conception
parental
occupation
and
exposure
-Maternal
drug intake
-Maternal
infections
-Maternal
medical
disorders
Details of
fetal
movement
Details of
previous
losses

11. Review Records of Previous Affected Children
Prenatal ultrasound records.
Events at birth including fetal distress, oligohydramnios or polyhydramnios, birth
weight, length and head circumference, and neonatal behavior and feeding history
should be sought.
Details of development history and behavior with formal assessment are very
important.

12. Abnormal Screening Results

13. Results of Any Invasive Procedures

14. Examination of the Fetus
Single
Primary
Defect
Multiple
Birth
Defects
1st step
to determine
the nature
and pattern
of anomalies

15. Prenatal diagnosis methods:
• INVASIVE TESTING:
– CVS.
– Amniocentesis.
– Cordocentesis.
– Embryo-fetoscopy
– Fetal tissue sampling.
• PGD & PGS
• NON-INVASIVE TESTING
• Fetal imaging:
– Ultrasound & Doppler.
– Fetal echocardiography.
– Fetal MRI.
• Maternal serum biochemical markers .
• Separation of fetal cells from maternal
circulation (NIPT; NIPD).

17. Prenatal Genetic Diagnostic Tests

18. From Cell to Gene

19. Chromosomal aberration vs Gene mutation

20. Chromosomal analysis
Typically defined
chromosomal
syndrome
(Trisomy 21)
Multiple
malformations
recurrent
spontaneous
miscarriage
Cystic
Hygroma
Parent carrier of
balanced
chromosomal
rearrangement

21. Techniques of chromosomal analysis

22. Advances in analysis of chromosomal aberrations

23. Indications of
array CGH
2 or more
ultrasound
abnormalities
including IUGR
CNS or
Dysmorphic
facial features
Limitations of
array CGH
Small changes in
the sequence of
single genes
(mutations)
Balanced
chromosomal
rearrangements
Array CGH

24. Molecular Diagnostic Tests
(single gene
monogenic- disorders)

25. Indications for Molecular (DNA) diagnostics
Confirm
diagnosis
of single
gene
disorders
Prenatal
diagnosis in
future
pregnancies
PGD
Carrier
testing

26. Advances in the prenatal diagnosis for single gene
disorders
•Using cffDNA
NIPD for
single gene
disorders
•CVS
•amniocentesis
Exome
Sequencing for
PND of fetal
anomalies

27. Recent advances in prenatal molecular diagnosis
Offer specific panels of WES (Whole Exome Sequencing ) when
structural fetal anomalies are detected on ultrasound examination
(esp Hydrops fetalis )

28. The challenging aspects of Pandora's pregnancy:
(A new era for prenatal genetic testing)

29. Exome Sequencing has Accelerated Gene
Discovery in Developmental Disorders
Contribution of
exome
sequencing in
Single gene
disorders

30. The challenge of novel Prenatal phenotypes
Non-specific findings
(imaging limitations )+
Clinical heterogeneity
New phenotypes of
unknown conditions
Lethal prenatal
phenotypes not present
in the database &
literature
(loss of function alleles)

31. The challenge of novel Prenatal phenotypes

32. Exome sequencing in Dysmorphic fetuses
• Small cohorts
• Multiple anomalies (25-80%)
diagnostic yield
• Increased NT alone (6.5% yield)
• Challenge of fetal phenotyping
• Trio exome
• Multidisciplinary team approach,
guidelines for eligibility, pretest
counseling, return of results.

33. Counseling dilemmas in era of modern molecular genetics
Results reported
on fetal samples
Disease
genes related
to the
prenatal
indication
Pathogenic
variants
Likely
pathogenic
VOUS
Disease genes
unrelated to
prenatal
indications
but likely to
cause disease
during
childhood
Pathogenic
variants
Likely
pathogenic
2ry or Incidental
findings

34. FETAL MRI

35. Biochemical laboratory tests
• mucopolysaccharidoses
(e.g., Hurler syndrome
Storage
disorders
• (Smith-Lemli-Opitz
syndrome
Disorders of
cholesterol
metabolism
• Zellweger syndrome,
chondrodysplasia
punctata
Peroxisomal
disorders

36. In the absence of a definitive diagnosis....
Expert perinatal pathology is required .

37. Post-mortum management of fetal
anomalies
Gross physical exam
Fetal tissue (blood, skin)
for karyotyping
DNA extraction for DNA
banking
Placenta & baby swab for
microbiology & virology
Baby photos
Baby gram
(whole body X-ray

39. ART related birth defects
• Epigenetic modifications
related to ART itself or
underlying reasons
• Higher rate of imprinting
syndromes (BWS, PWS,
RSS).

40. Take home messages
Multidisciplinary team approach
More information ……more challenges
Shared decision-making process
1st prenatal visit
Promote reproductive choices
pre- and post-test counseling
Fetal specific panels
Training & educating health care providers

41. Phenotype (clinical
manifestation)
Pattern recognized
No
Diagnostic
dead end
Emperic
recurrence
estimate
Yes
Category of disease : genetic heterogeneity
Monogenic
Gene mapped
Gene identified
Definitive molecular
diagnosis
Complex- multigenic
Emperic recurrence
estimate
Genetic
counseling
Aneuploidy/ aneusomy
Chromosomal analysis
Definitive diagnosis
Precise risk
determination