Are cheek swab DNA tests reliable for detecting genetic, exome, and array abnormalities in individuals, particularly those with a family history of genetic disorders?

Reliability of Cheek Swab DNA Tests for Genetic Testing

Yes, cheek swab (buccal) DNA tests are reliable for most genetic testing applications, including chromosomal microarray analysis and exome sequencing, with the critical caveat that they should NOT be used in patients with active hematologic malignancies or post-allogeneic hematopoietic stem cell transplant recipients. 1

Sample Quality and DNA Yield

Buccal swab samples provide high-quality DNA suitable for genetic testing:

• DNA yield from buccal swabs is substantially higher than dried blood spots, with mean concentrations of 70.2 ng/μL compared to 16.0 ng/μL from capillary blood samples (p < 0.001). 2
• The quality of DNA obtained from buccal swabs is comparable to blood samples, with highly reproducible melting curve analyses demonstrating adequate DNA integrity for genotyping and sequencing applications. 2
• Buccal swabs are particularly advantageous for noninvasive sampling, making them ideal for pediatric populations and repeated sampling scenarios. 1

Applications in Chromosomal Microarray Analysis

Buccal swab DNA is appropriate for chromosomal microarray analysis (CMA) with specific considerations:

• CMA is recommended as a first-line test for multiple anomalies, developmental delays, and autism spectrum disorders, and buccal swab DNA is suitable for this testing. 3, 4
• CMA detects copy number variations at 50-100 kb resolution with approximately 10% diagnostic yield, significantly higher than conventional karyotyping's 3.7% yield. 4
• Important limitations include inability to detect balanced chromosomal rearrangements (translocations, inversions), low-level mosaicism below 20-30%, and some aneuploidies like XYY if wrong gender controls are used. 3, 4

Applications in Exome and Genome Sequencing

Buccal swab DNA performs well for next-generation sequencing applications:

• Whole-exome sequencing achieves a 25% molecular diagnostic rate in patients with suspected genetic disorders, with most being children with neurologic phenotypes. 5
• Genome sequencing provides an additional 8% diagnostic yield beyond exome sequencing, identifying variants requiring genome-level analysis including intronic variants, structural variants, and tandem repeat expansions. 6
• Multiple genetic diagnoses can be identified in a single patient, with 4.6-7% of cases revealing two or more distinct genetic conditions, emphasizing the importance of thorough data curation. 7

Critical Contraindications and Pitfalls

Avoid buccal swabs in these specific scenarios:

• Active hematologic malignancies: Buccal samples contain leukocyte-derived DNA with dysplastic cells, contaminating germline testing. Instead, obtain skin biopsy at the time of bone marrow biopsy. 1
• Post-allogeneic HSCT recipients: Donor-derived cells progressively replace the patient's buccal epithelial cells over time, risking DNA contamination. Use fibroblasts from skin biopsy instead. 1
• Suspected sex chromosome aneuploidies requiring rapid diagnosis: Traditional karyotyping from blood is superior for detecting mosaicism and provides faster turnaround times (48 hours vs. 3-5+ days for array analysis). 3, 4

When to Choose Alternative Testing Methods

Conventional karyotyping from blood is more appropriate when:

• Common aneuploidies are suspected (trisomy 21,18, sex chromosome abnormalities). 3
• Family history of balanced chromosomal rearrangements exists. 3
• Multiple miscarriages require evaluation. 3
• Low-level mosaicism is clinically suspected, as karyotyping detects mosaicism at 10% level for whole chromosome abnormalities versus 20-30% for CMA. 3, 4

Practical Recommendations for Test Selection

Follow this algorithmic approach:

1. For developmental delays, multiple anomalies, or autism spectrum disorders: Order CMA using buccal swab DNA as first-line testing. 3, 4

2. If CMA is normal but clinical suspicion remains high: Proceed to exome sequencing using the same buccal swab DNA, which identifies causative variants in 25% of cases. 5

3. If exome sequencing is nondiagnostic: Consider genome sequencing, which provides an additional 8% diagnostic yield for variants not detectable by exome analysis. 6

4. Ensure appropriate follow-up: When chromosomal imbalances are identified, perform parental FISH studies to rule out balanced rearrangements with up to 50% recurrence risk. 3