What precautions should a couple with a history of a child with William syndrome, born from a consanguineous (related by blood) marriage, take if they want to get pregnant again?

Preconception Counseling and Management for Consanguineous Couples with a Child with Williams Syndrome

This couple requires immediate referral to medical genetics for comprehensive genetic counseling before attempting another pregnancy, as consanguineous unions increase baseline risk for autosomal recessive conditions, though Williams syndrome itself carries a negligible recurrence risk in this scenario. 1

Understanding Williams Syndrome Inheritance in This Context

Williams syndrome is a de novo deletion in approximately 95% of cases, meaning the recurrence risk for this couple is extremely low (near general population risk of 1 in 7,500). 2 The consanguinity is essentially unrelated to the occurrence of Williams syndrome in their first child, as this is typically a spontaneous chromosomal deletion event, not an inherited autosomal recessive condition. 1

However, the consanguineous relationship does independently increase their baseline risk for:

• Autosomal recessive genetic disorders (3-6% above baseline depending on degree of relatedness) 1, 3
• Birth defects and developmental disabilities from shared recessive alleles 3, 4

Mandatory Preconception Steps

1. Medical Genetics Referral (Highest Priority)

Refer to a medical genetics specialist or genetic counselor immediately for comprehensive preconception counseling. 1 This is explicitly recommended by the American College of Medical Genetics for consanguineous unions to review pedigree, assess degree of relatedness, and discuss potential fetal risks and testing options. 1

The genetics consultation should address:

• Detailed three-generation pedigree construction to identify any autosomal recessive conditions in the extended family 3
• Calculation of coefficient of relationship (first cousins share 1/8 of genes; closer relationships carry higher risk) 5, 6
• Discussion of the 50% transmission risk IF the affected child's Williams syndrome were inherited (which is unlikely given it's typically de novo) 2, 7
• Clarification that consanguinity did not cause the Williams syndrome 1

2. Ethnicity-Based Carrier Screening

Offer expanded carrier screening based on the couple's ethnic background, as consanguineous couples should receive the same ethnic-specific screening as any couple from their population. 3, 4 This includes:

• Hemoglobinopathies (sickle cell, thalassemia) if indicated by ethnicity 1, 3
• Tay-Sachs disease for Ashkenazi Jewish, French Canadian, or Cajun ancestry 1
• Cystic fibrosis carrier screening 1, 3
• Other conditions based on ethnic background 3

3. Confirm Williams Syndrome Diagnosis in First Child

Verify that the affected child's Williams syndrome diagnosis was confirmed by chromosomal microarray, FISH, or MLPA showing the typical 7q11.23 deletion. 1, 2 This is critical because:

• Atypical deletions or single-gene mutations (ELN only) may have different inheritance patterns 1
• If only the ELN gene is affected, this represents supravalvular aortic stenosis (SVAS), which is autosomal dominant with 50% recurrence risk 1

Prenatal Monitoring Recommendations

During Pregnancy

If the couple proceeds with pregnancy, offer enhanced prenatal surveillance beyond routine care: 1, 3

• First and second trimester maternal serum screening and nuchal translucency measurement 1, 3
• High-resolution fetal ultrasonography (level II anatomy scan) at 18-20 weeks to detect structural anomalies 3
• Fetal echocardiography if any cardiac concerns arise, given the cardiovascular manifestations in their first child 1
• Consider amniocentesis or chorionic villus sampling with chromosomal microarray if structural anomalies detected 1

Prenatal Testing Options to Discuss

Present the option of prenatal diagnostic testing (CVS at 10-13 weeks or amniocentesis at 15-20 weeks) with chromosomal microarray, though emphasize the low recurrence risk for Williams syndrome specifically. 1 The primary value of prenatal testing in this case is:

• Detecting other chromosomal abnormalities (baseline risk)
• Identifying autosomal recessive conditions if specific family history concerns exist 1
• Providing reassurance given their previous experience 6

Newborn Screening Considerations

If prenatal testing is declined, ensure enhanced newborn evaluation: 3

• Newborn hearing screening 3
• Standard newborn metabolic screening for treatable inborn errors of metabolism 3
• Clinical examination for dysmorphic features or congenital anomalies 3
• Pediatric cardiology evaluation if any murmur or cardiovascular concerns 1, 2

Critical Counseling Points

Address Psychological Concerns

Acknowledge the couple's anxiety about recurrence and provide accurate risk information to reduce unnecessary worry. 6 Studies show genetic counseling for consanguinity reduces anxiety and empowers couples with accurate information. 6

Family Screening Recommendation

Screen available family members for undetected Williams syndrome features (hypertension, supravalvular aortic stenosis, coronary disease risk), as there is a 25% chance that parents of children with Williams syndrome carry a chromosomal inversion that increases risk. 1 This inversion is present in 6% of the general population but 25% of parents of affected children. 1

Document Informed Decision-Making

Ensure non-directive counseling that respects the couple's autonomy while providing complete medical information. 5, 6 Options include:

• Natural conception with or without prenatal testing 5, 3
• Preimplantation genetic testing (PGT-M) if specific autosomal recessive concerns identified 1
• Donor gametes if couple desires to eliminate consanguinity-related risks 5

Common Pitfalls to Avoid

• Do not overstate the recurrence risk for Williams syndrome—it is near baseline unless parental chromosomal studies show abnormalities 1, 2
• Do not underestimate the independent risk from consanguinity for autosomal recessive conditions unrelated to Williams syndrome 1, 3
• Do not proceed with pregnancy planning without formal genetics consultation 1
• Do not assume the Williams syndrome is inherited without confirming the genetic mechanism 1