What is the recommended screening method for deletion of 22q11.2 (chromosome 22q11.2 deletion syndrome)?

Recommended Screening Methods for 22q11.2 Deletion Syndrome

The recommended first-line screening method for 22q11.2 deletion syndrome is multiplex ligation-dependent probe amplification (MLPA) or chromosomal microarray analysis (CMA), with fluorescence in situ hybridization (FISH) as an alternative when these methods are unavailable. 1

Diagnostic Testing Options

Primary Recommended Methods

1. Multiplex Ligation-dependent Probe Amplification (MLPA)

   • High sensitivity for detecting typical and atypical deletions
   • Cost-effective compared to microarray
   • Recommended as first-line testing in most clinical settings

2. Chromosomal Microarray Analysis (CMA)

   • Detects both typical and atypical deletions
   • Provides precise information about deletion size and boundaries
   • Can detect additional genomic imbalances
   • Particularly useful when comprehensive genomic analysis is needed

3. Fluorescence In Situ Hybridization (FISH)

   • Acceptable alternative when MLPA or microarray are unavailable
   • More limited in detecting atypical or smaller deletions
   • Historical method but still clinically valid

Clinical Indications for Testing

Testing for 22q11.2 deletion should be considered in individuals with:

• Congenital heart defects, particularly conotruncal anomalies (9.4% positive rate) 2
• Hypocalcemia (33.3% positive rate) 2
• Characteristic dysmorphic features (6.4% positive rate) 2
• Velopharyngeal insufficiency or submucous cleft palate
• Immunodeficiency
• Developmental delay or learning difficulties
• Family history of 22q11.2 deletion syndrome

Prenatal and Newborn Screening

Prenatal Screening Options

• Noninvasive prenatal screening (NIPS) using cell-free DNA has shown:
  • 75-83.3% sensitivity for 22q11.2 deletions
  • 99.84% specificity
  • Positive predictive value of 23.7-52.6% 3
  • Can be performed from 10 weeks gestation 4

Prenatal Diagnostic Testing

• Chorionic villus sampling or amniocentesis with chromosomal microarray analysis is recommended for definitive prenatal diagnosis 4
• Indicated for:
  • Abnormal NIPS results suggesting 22q11.2 deletion
  • Parent or previous child with 22q11.2 deletion
  • Prenatal ultrasound findings suggestive of 22q11.2DS (conotruncal heart defects, thymic hypoplasia)

Newborn Screening

• T-cell receptor excision circle (TREC) assay, used in severe combined immunodeficiency (SCID) screening programs, can incidentally detect 22q11.2 deletion syndrome 5
• This represents an opportunity for early diagnosis in some cases

Important Considerations

• The 22q11.2 region contains low copy repeats (LCRs) that predispose to deletions of varying sizes
• Most patients have a deletion between LCR22-A and LCR22-D (typical ~3Mb deletion)
• Smaller nested deletions (≥500kb) within this region can also cause the syndrome 3
• Central deletions (LCR22-B to LCR22-D) have a different phenotypic profile with lower prevalence of congenital heart anomalies 6

Clinical Pitfalls to Avoid

• Do not rely solely on clinical features for diagnosis as the phenotype is highly variable
• Do not use FISH as first-line testing when MLPA or microarray are available, as FISH may miss atypical or smaller deletions
• Do not dismiss the possibility of 22q11.2 deletion in patients with isolated features (e.g., isolated hypocalcemia)
• Do not forget to test parents of affected individuals, as ~10% of cases are inherited
• Do not overlook the need for genetic counseling for reproductive planning, as there is a 50% risk of transmission from an affected parent 4

Follow-up After Diagnosis

Once diagnosed, patients should receive comprehensive evaluation according to established guidelines, including:

• Cardiac evaluation with echocardiogram and EKG
• Calcium, PTH, and thyroid function testing
• Immunologic assessment with T- and B-cell phenotyping
• Developmental and neuropsychiatric evaluation
• Referral to a multidisciplinary 22q11.2 deletion syndrome clinic when available 1