CNV Interpretation
5 sections · 30 min
Copy Number Variants: Definition and Clinical Significance
Copy number variants (CNVs) are structural genomic variants in which a segment of DNA is present at a copy number that differs from the normal diploid state. CNVs range from kilobases to megabases in size and can involve deletions (loss) or duplications (gain). They are a major source of both normal human genomic variation and serious neurogenetic disease.
Key Points
- CNV classification by size: chromosomal microarray typically detects CNVs ≥50–200 kb; WGS can detect CNVs as small as a few hundred base pairs
- Population CNVs: many CNVs are common (>1% frequency) and benign; catalogued in the Database of Genomic Variants (DGV) and gnomAD-SV
- Pathogenic CNVs: typically rare (<0.01%), larger, and encompass genes with established disease associations
- CNVs account for ~15–20% of diagnoses in intellectual disability and autism spectrum disorder — the highest yield for any single variant class
✦ Check Your Understanding
Which of the following CNVs would be MOST strongly supported as pathogenic based on ACMG/ClinGen framework evidence?
Select an answer to reveal the explanation
Detection Technologies: CMA and WGS
Multiple platforms can detect CNVs, each with distinct strengths and limitations. Understanding the technical basis of each platform is essential for interpreting reported CNVs and recognizing their potential artifacts.
Key Points
- Chromosomal Microarray (CMA): two main types — array CGH (comparative genomic hybridization) and SNP arrays. SNP arrays additionally detect copy-neutral LOH and segmental UPD
- WGS for CNV detection: uses read-depth analysis, split reads, and discordant read pairs; superior sensitivity for smaller CNVs and breakpoint resolution
- CMA limitations: cannot detect balanced rearrangements (inversions, balanced translocations), small variants (<50 kb), repeat expansions, or low-level mosaicism (<10–15%)
- WGS limitations for CNVs: bioinformatic complexity; coverage uniformity affects sensitivity in GC-rich regions and segmental duplications
✦ Check Your Understanding
What mechanism generates recurrent CNVs at loci flanked by segmental duplications?
Select an answer to reveal the explanation
ACMG/ClinGen CNV Classification Framework
The ACMG and ClinGen jointly published the technical standards for interpretation of constitutional CNVs in 2019 (Riggs et al., Genetics in Medicine). This framework uses a scoring system based on five evidence domains to assign one of five pathogenicity classifications, directly analogous to the 5-tier ACMG/AMP variant classification system.
Key Points
- Five-tier classification: Pathogenic (P), Likely Pathogenic (LP), Uncertain Significance (VUS), Likely Benign (LB), Benign (B)
- Evidence domain 1: Initial assessment — size of CNV and gene content (coding vs. non-coding)
- Evidence domain 2: Overlap with established pathogenic or benign CNV regions (OMIM, ClinVar, ISCA/ClinGen, DGV)
- Evidence domains 3–5: Functional/phenotypic evidence (gene dosage sensitivity, inheritance data, phenotype match)
- Haploinsufficiency (HI) score and triplosensitivity (TS) score from ClinGen assess how tolerant each gene is to loss or gain of a single copy
✦ Check Your Understanding
According to the ClinGen CNV dosage sensitivity framework, which finding most strongly supports pathogenicity of a deletion CNV?
Select an answer to reveal the explanation
Recurrent Genomic Disorders in Neurogenetics
Recurrent CNVs arise at specific genomic loci flanked by segmental duplications (low-copy repeats) through non-allelic homologous recombination (NAHR) during meiosis. These 'genomic disorders' produce stereotyped phenotypes and account for a substantial fraction of neurogenetic diagnoses.
Key Points
- 22q11.2 deletion syndrome (DiGeorge/velocardiofacial): ~3 Mb deletion; conotruncal heart defects, palatal abnormalities, developmental delay, schizophrenia risk (1/4,000 births)
- Williams-Beuren syndrome: ~1.5 Mb deletion at 7q11.23; hypersociability, intellectual disability, supravalvular aortic stenosis; caused by haploinsufficiency of ELN and other genes
- 1p36 deletion syndrome: most common subtelomeric deletion; severe intellectual disability, hypotonia, seizures, heart defects
- 15q11–q13: parent-of-origin dependent — maternal deletion → Angelman syndrome; paternal deletion → Prader-Willi syndrome; maternal duplication → autism spectrum disorder
✦ Check Your Understanding
A CNV is found that overlaps with a region of known parent-of-origin effects. The deletion is found on the maternally inherited chromosome 15 at 15q11–q13. The most likely diagnosis is:
Select an answer to reveal the explanation
CNV Reporting and Clinical Communication
Accurate and clinically actionable reporting of CNVs requires consistent use of standardized nomenclature (ISCN/HGVS), appropriate evidence-based classification, and clear communication of clinical implications to referring clinicians and patients.
Key Points
- ISCN/HGVS nomenclature: report CNV coordinates using a current genome build (GRCh38 preferred); include gene content summary
- Parental studies: testing parents (inheritance) provides critical evidence — de novo CNVs are ~10-fold more likely to be pathogenic than inherited CNVs
- VUS CNVs: communicate clearly that VUS cannot be used clinically; offer follow-up parental testing and plan for reclassification review
- Incidental findings: CMA may reveal clinically significant CNVs unrelated to the indication; pre-test counseling should address this possibility
✦ Check Your Understanding
A 2.5 Mb deletion at 22q11.2 is identified in a child with conotruncal heart defect, cleft palate, and developmental delay. This most likely represents:
Select an answer to reveal the explanation
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