Can parents with a history of a child with fetal anomalies undergo genetic investigations?

Genetic Investigations for Parents with a History of a Child with Fetal Anomalies

Yes, parents who have had a previous child with fetal anomalies should undergo genetic investigations to identify potential genetic causes and assess recurrence risks for future pregnancies. 1

Rationale for Genetic Investigations

Parents with a history of a child with fetal anomalies should pursue genetic testing for several important reasons:

• To identify potential genetic causes of the anomalies
• To determine recurrence risks for future pregnancies
• To enable informed reproductive decision-making
• To guide prenatal testing in subsequent pregnancies

Recommended Genetic Investigations

For the Parents:

1. Karyotype analysis:

   • Particularly important to identify balanced translocations or chromosomal rearrangements that could lead to unbalanced offspring 1
   • Especially indicated when there have been multiple pregnancy losses or a child with chromosomal abnormalities 1

2. Carrier screening:

   • For autosomal recessive conditions relevant to the specific anomalies observed 1
   • May include targeted gene panels based on the specific anomalies

3. Skin biopsy with cytogenetic analysis:

   • Indicated when blood karyotype is normal but suspicion of chromosomal mosaicism remains high
   • Particularly useful when parents have had more than one child with the same chromosomal aberration (e.g., trisomy 21) 1

For the Affected Child/Fetus (if available):

1. Comprehensive chromosomal analysis:

   • Minimum 550-band resolution karyotype 1
   • Microarray testing for submicroscopic deletions/duplications

2. Specific genetic testing:

   • FISH testing for suspected microdeletion/microduplication syndromes 1
   • Exome sequencing if standard testing is negative (can identify diagnoses in approximately 20% of cases with fetal anomalies) 2

Special Considerations

• Consanguinity: If the parents are blood relatives, this increases the risk of autosomal recessive conditions and warrants specialized genetic counseling 1

• Multiple pregnancy losses: Parents with a history of recurrent pregnancy losses (more than two) should be evaluated for chromosomal rearrangements, which account for 5-7% of such cases 1

• Type of anomaly: The specific anomaly in the previous child should guide the genetic investigations:

  • Birth defects like cleft lip/palate, spina bifida, or congenital heart defects
  • Mental retardation or autism
  • Multiple congenital anomalies suggesting a syndrome

Importance of Comprehensive Evaluation

When a fetal structural anomaly has been identified:

• A complete autopsy by a perinatal or pediatric pathologist provides maximum information for diagnosis and determining etiology 3
• If complete autopsy is refused, at least a partial or external examination (including X-rays and photographs) should be encouraged 3
• Comprehensive newborn assessment is essential for diagnosis and counseling on etiology, prognosis, and recurrence risk 3

Genetic Counseling

Genetic counseling is a crucial component of the process and should include:

• Discussion of recurrence risks based on identified or suspected genetic causes
• Explanation of testing options for future pregnancies
• Information about preventive measures where applicable (e.g., folate supplementation)
• Support for informed reproductive decision-making

Pitfalls and Caveats

• Normal testing doesn't eliminate risk: Even with normal karyotype and microarray results, the fetus may have a genetic syndrome, sequence, or association that isn't detectable by standard testing 3

• Tissue-limited mosaicism: Some chromosomal abnormalities may not be present in blood lymphocytes but may be detected in skin fibroblasts 1

• Variant interpretation challenges: Genetic testing, especially exome sequencing, may identify variants of uncertain significance that require careful interpretation 2

By pursuing appropriate genetic investigations, parents who have had a child with fetal anomalies can gain valuable information about recurrence risks and options for future pregnancies, ultimately improving reproductive outcomes and reducing morbidity and mortality in future offspring.