When should a patient with congenital heart disease, cleft palate, developmental delays, or recurrent infections due to suspected immunodeficiency, and/or a family history of 22q11 microdeletion, screen for 22q11 microdeletion?

When to Screen for 22q11.2 Microdeletion

All newborns and infants with conotruncal heart defects (interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, conoventricular/conoseptal hypoplasia/malalignment VSD with aortic arch anomaly, isolated aortic arch anomaly, or discontinuous pulmonary arteries) should undergo FISH testing for 22q11.2 microdeletion before surgical intervention, regardless of whether facial dysmorphisms or other suggestive features are present. 1

Cardiac Indications for Screening

Conotruncal Anomalies (Highest Priority)

• Screen all patients with:
  • Interrupted aortic arch 1
  • Truncus arteriosus 1
  • Tetralogy of Fallot 1
  • Conoventricular, conoseptal hypoplasia, or malalignment VSD with aortic arch anomaly 1
  • Isolated aortic arch anomaly 1
  • Discontinuous pulmonary arteries 1

The American Heart Association recommends testing occurs before surgical intervention to inform perioperative management and genetic counseling. 1 Research demonstrates 22q11.2 microdeletion occurs in 9.4-22.5% of patients with conotruncal defects. 2, 3

Non-Conotruncal Heart Defects

• Screen when accompanied by at least one additional 22q11.2DS feature (facial dysmorphism, hypocalcemia, thymic hypoplasia, developmental delay, cleft palate). 4
• Deletion frequency in non-conotruncal defects with additional features is approximately 11.5%. 4

Non-Cardiac Indications for Screening

Hypocalcemia

• Screen all patients with unexplained hypocalcemia, particularly when associated with hypoparathyroidism. 2
• 33.3% of patients with hypocalcemia have 22q11.2 deletion. 2
• Hypocalcemia occurs in 62% of patients with confirmed deletion. 3

Cleft Palate and Palatal Anomalies

• Screen when cleft palate occurs in combination with congenital heart disease, developmental delays, or characteristic facial features. 1
• Do not screen for isolated cleft palate without additional features, as research shows 0% deletion rate in isolated palatal anomalies. 2

Developmental Delays and Intellectual Disability

• Screen when developmental delay occurs with:
  • Hypotonia 1
  • Failure to thrive (not related to CHD) 1
  • Microcephaly 1
  • Multiple congenital anomalies 1
  • Facial dysmorphia 1

Recurrent Infections and Suspected Immunodeficiency

• Screen when recurrent infections occur with:
  • Thymic hypoplasia or aplasia on imaging 1, 5
  • CD3+ T lymphocytes <1500 cells/μL 5
  • Persistent candidiasis 5
  • History suggesting T-cell deficiency 1

Characteristic Facial Dysmorphism

• Screen when dysmorphic features suggestive of 22q11.2DS are present, even without other major anomalies. 2
• 6.4% of patients with isolated dysmorphic traits have confirmed deletion. 2
• Facial dysmorphism is present in 92% of patients with deletion. 3

Prenatal Screening

Perform prenatal genetic testing (amniocentesis or chorionic villus sampling with FISH or multiplex ligation-dependent probe amplification) when fetal ultrasound identifies conotruncal anomalies. 1

Previously Untested Patients

Any child, adolescent, or adult with interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, VSD, or aortic arch anomaly not previously tested should undergo screening for 22q11.2 microdeletion. 1

Family Screening

• Test both parents when a child is diagnosed with 22q11.2 deletion to determine if inherited (10% of cases) or de novo (90% of cases). 1
• Approximately 6-6.25% of parents will have the deletion, often with mild or subtle features. 3, 4
• Affected individuals have 50% recurrence risk for offspring. 1, 6, 5

Testing Methodology

• First-line testing: MLPA (multiplex ligation-dependent probe amplification) or chromosomal microarray for the proband. 1
• Alternative: FISH if MLPA/microarray unavailable. 1
• Parental testing: MLPA or FISH. 1

Critical Pitfalls to Avoid

• Do not wait for multiple features to be present before testing patients with conotruncal defects—test at diagnosis regardless of other findings. 1
• Do not assume isolated findings exclude 22q11.2DS—variable expressivity means patients may have subtle or few features. 1, 7
• Do not overlook parental testing—failure to identify affected parents prevents accurate recurrence risk counseling. 1
• Do not screen isolated cleft palate without additional features—this has zero yield. 2