What are the clinical implications and management strategies for copy number variants (CNVs) in the C3 gene?

Clinical Implications and Management of Copy Number Variants in the C3 Gene

Copy number variants (CNVs) in the C3 gene should be carefully evaluated for their potential impact on complement dysregulation, which may contribute to diseases like C3 glomerulopathy and requires specialized complement testing for proper diagnosis and management. 1

Understanding CNVs in the C3 Gene

• CNVs are a form of structural variation in the human genome that can involve deletions, duplications, or complex rearrangements of genomic segments, potentially affecting gene function and phenotypic expression 2
• C3 gene CNVs may disrupt normal complement pathway regulation, which is critical for immune function and can lead to complement-mediated disorders when dysregulated 1
• The evaluation of CNVs should consider both their size and genomic content, as even small CNVs can be clinically significant if they involve dosage-sensitive genes like C3 2

Technical Considerations for CNV Detection

• Next-generation sequencing (NGS) approaches are commonly used to detect CNVs, including targeted gene panels (TGPs), virtual gene panels based on exome sequencing (ES), or genome sequencing (GS) 2
• For accurate CNV detection, laboratories should ensure adequate coverage of the C3 gene region, with the ability to detect both gains and losses of genomic material 2
• To maximize clinical sensitivity, laboratories should incorporate ancillary assays such as Sanger sequencing to fill in missing content or other methods to detect CNVs and large structural variants 2
• The analytical sensitivity target should be 99% for CNVs ≥400 kb in size, with a false-positive rate of ≤1% 2

Clinical Evaluation of C3 Gene CNVs

• When a CNV involving the C3 gene is detected, careful evaluation of the genomic content is essential to determine its clinical significance 2
• Consider whether the CNV contains unique, gene-rich sequence that may affect C3 gene function or expression 2
• Evaluate whether the CNV results in haploinsufficiency, gain of function, or disruption of regulatory elements that could impact complement pathway regulation 2
• Compare the identified CNV with internal and external databases to determine if it represents a known pathogenic variant or benign polymorphism 2

Diagnostic Workup for Suspected C3-Related Disorders

• For patients with suspected C3-related disorders like C3 glomerulopathy, a thorough evaluation should be completed to identify the underlying cause, including screening for infections, autoimmune diseases, and monoclonal gammopathies 1
• Specialized complement testing should be considered to identify complement dysregulation, which may be associated with C3 gene CNVs 1
• In adults, particularly those over 50 years old, serum and urine immunoelectrophoresis, immunofixation, and serum free light chain analysis should be performed 1

Management Strategies Based on CNV Assessment

• Treatment approaches should be tailored based on the specific clinical manifestations associated with the C3 gene CNV 1
• For moderate-to-severe C3 glomerulopathy without monoclonal gammopathy, initial treatment with mycophenolate mofetil plus glucocorticoids is recommended 1
• For patients who fail first-line therapy, complement-targeting therapies like eculizumab or pegcetacoplan may be considered 1
• In cases with monoclonal gammopathy, treatment should focus on controlling the clone of B cells or plasma cells responsible for production of the monoclonal immunoglobulin 1

Reporting and Interpretation Considerations

• When reporting C3 gene CNVs, laboratories should clearly state the detected variant, its size, genomic coordinates, and genes involved 2
• The clinical significance of the CNV should be assessed based on available evidence, including known associations with disease phenotypes 2
• Avoid inferring a pathogenic role based solely on predicted gene function without sufficient evidence in the human population 2
• For variants of uncertain significance, periodic reassessment is recommended as new information becomes available 2

Common Pitfalls and Considerations

• Failure to accurately map CNV breakpoints may lead to misinterpretation of the variant's clinical significance 2
• Misclassification of benign CNVs as pathogenic or vice versa can result in inappropriate clinical management 2
• Heterochromatic and euchromatic variants in the C3 gene region may be misinterpreted as pathogenic CNVs 3
• The artificial separation of submicroscopic CNVs and cytogenetically visible CNVs may lead to inconsistent interpretation 3
• The "two-hit model" suggests that combinations of individually harmless CNVs may lead to clinical manifestations when present together, highlighting the importance of comprehensive genomic evaluation 3