PMC Arrhythmogenic Cardiomyopathy Panel

Methodology

Targeted Exome/ Slice Exome (Next Generation Sequencing including Copy Number Variation)

Assay Information
- ACTN2: Deletion/duplication analysis is not offered for exon 9.
- ANKRD1: Deletion/duplication analysis is not offered for exons 3-4. Sequencing analysis for exons 4 includes only cds +/- 10 bp.
- FLNC: Deletion/duplication analysis is not offered for exon 47. Sensitivity and specificity for single nucleotide variants| insertions and deletions in exons 47-48 may be reduced due to the presence of segmental duplications overlapping the region.
- TTN: Exons 45-46| 147| 149| 164| 172-201 (NM_001267550.2) are excluded from analysis. TTN variants are included in the primary report based on functional effect and/or location. A complete list of variants of uncertain significance| likely benign and benign variants in TTN is available upon request. Variants are named relative to the NM_001267550.2 (meta) transcript. Variants in the coding sequence and intronic boundaries of the clinically relevant NM_133378.4 (N2A) and fetal isoforms are reported (PMID: 25589632| 29598826| 29691892| 31660661)| with the exception of the PEVK tandem repeat region (172-198) (PMID: 28040389).

Limitations

All sequencing technologies have limitations. A negative result from this analysis does not rule out a possible genetic diagnosis as some variants may not be detected by this test. This test is not designed to detect low level mosaicism, structural rearrangements, indels >40bp, deep intronic variants of unknown clinical significance, or large cytogenetic CNVs. Certain inherent qualities of the human genome, for example repetitive regions/homopolymers, GC rich, pseudogenes, and rare polymorphisms, pose significant technical challenges such as sequence misalignment that may potentially impact the accuracy of the results. False negative results may also occur in the setting of allogeneic bone marrow, stem cell transplantation, active or chronic hematologic conditions, recent blood transfusions, suboptimal DNA quality or PCR trace contamination. Other potential sources of error include sample mix-ups and clerical issues.