What are the guidelines for pregenetic (pre-genetic) testing?

Guidelines for Pregenetic Testing

Pregenetic testing requires comprehensive genetic counseling before and after testing, with specific referral criteria based on personal and family history, age, ethnicity, and reproductive goals.

Indications for Genetic Referral

Prenatal/Preconceptional Indications

• Advanced maternal age: ≥35 years at delivery for singleton pregnancies; ≥33 years for twin pregnancies 1, 2
• Consanguinity: Couples who are close blood relatives 1
• Abnormal screening tests: Abnormal maternal serum screening or nuchal translucency 1
• Teratogen exposure: Radiation, high-risk infections, drugs, medications, alcohol 1
• Fetal anomalies: Identified on ultrasound or echocardiography 1
• Positive carrier screening: For conditions like cystic fibrosis, thalassemia, sickle cell anemia, Tay-Sachs 1
• Adverse pregnancy history: Stillbirths, hydrops, recurrent pregnancy losses (>2), SIDS 1

Family History Indications

• Known genetic disorders: Family members with identified mutations 1
• Cancer predisposition: Meeting Amsterdam criteria, revised Bethesda guidelines, or ≥5% risk prediction for Lynch Syndrome 1
• Ethnic background: Ashkenazi Jewish ancestry (carrier screening for Tay-Sachs, Gaucher disease, etc.) 1

Pregenetic Counseling Process

Components of Genetic Counseling

• Collection of personal and family medical history 1
• Education about the disorder 1
• Exploration of psychosocial dimensions 1
• Informed consent, including cost and risk of genetic discrimination 1
• Disclosure of test results 1
• Follow-up planning 1

Risk Assessment

Before genetic testing, clinicians should:

• Construct a pedigree tree relevant to the disorder 1
• Analyze disease severity, heterogeneity, and genotype-phenotype correlation 1
• Assess reproductive goals and options 1
• Evaluate medical history for conditions that could affect future pregnancies 1
• Review medication use for potential teratogens 1

Types of Pregenetic Testing

Carrier Screening

• Universal screening: Recommended for conditions like cystic fibrosis
• Ethnic-based screening: For Ashkenazi Jewish population (Tay-Sachs, Gaucher disease, etc.) 1
• Family history-based: When specific mutations are known in the family 1

Prenatal Diagnostic Testing

• Indicated when both parents have identifiable mutations for the same disorder 1
• Options include amniocentesis and chorionic villus sampling 3
• DNA samples should be obtained from both parents as controls 1

Preimplantation Genetic Testing (PGT)

• Appropriate for couples with high risk of gene transmission 1
• Requires multidisciplinary approach with genetic counseling experts 1
• Involves IVF/ICSI technology, embryo biopsy, and genetic analysis 1

Post-Testing Counseling

Results Interpretation

• Positive results should be promptly communicated (within one working day) 1
• Negative results should include clear interpretation 1
• Bayesian calculations should determine remaining carrier risk 1

Follow-up Recommendations

• For positive results: genetic counseling, targeted ultrasound, amniocentesis 1
• For negative results: explanation of limitations and residual risk 1
• For uncertain results: additional testing options 1

Special Considerations

De Novo Mutations

• When a child has a de novo pathogenic variant, consider PGT-M or prenatal diagnosis due to possible gonadal mosaicism 1
• If two or more instances of adverse gene variants exist in pregnancy history, PGT is appropriate 1

Folate Supplementation

• Preconceptional supplementation with folic acid reduces ONTD incidence by up to 80% 1
• Most North American locations can expect 20-30% reduction from fortification 1

Common Pitfalls to Avoid

• Inadequate pretest information: Collect complete personal/family history before testing 1
• Misinterpretation of results: Ensure proper training for healthcare professionals 1
• Insufficient counseling: Provide both pre- and post-test genetic counseling 1
• Delayed referral: Early referral is critical for timely intervention 2
• Overlooking family history: Family history is the cornerstone of genetic risk assessment 4
• Testing without clinical utility: Consider how results will impact management 5
• Expanding testing beyond evidence: New technologies should be applied only when supported by research 6

By following these guidelines, healthcare providers can ensure appropriate referral for pregenetic testing, comprehensive counseling, and proper interpretation of results to optimize patient outcomes.