Abstract 4128590: Identical Twins, Non-Identical Results: Genetic Testing for Cardiomyopathy

Case: A 58-year-old male (Twin A) with no medical history presented with syncope while playing paddle ball. TTE showed LVEF 15-20%. Cardiac MRI (CMR) identified transmural late gadolinium enhancement (LGE) in the inferolateral wall of the LV, but angiography showed non-obstructive CAD. Four years later, his monozygotic twin (Twin B), also with no medical history, suffered cardiac arrest while playing paddle ball. TTE showed LVEF 5-10%. CMR revealed inferolateral LGE (Figure 1) with angiography showing non-obstructive CAD. Genetic testing was performed by different companies. Twin A was found to be heterozygous for myosin light chain kinase 3 ( MYLK3 ) p.R380H (c.1139C>A), a variant of uncertain significance (VUS). While rare (gnomAD allele frequency 2.7e -4 ), MYLK3 p.R380H is not conserved across species, exchanges amino acids with similar biochemical properties, and is predicted to be benign by in silico pathogenicity tools. Notably, MYLK3 was not sequenced in Twin B, who was instead found to be heterozygous for desmoplakin ( DSP ) p.R1002W (c.3004C>T). DSP p.R1002W is highly conserved, exchanges amino acids with dissimilar properties, and is very rare (gnomAD allele frequency 2.8e -5 ). In silico testing yielded conflicting results with some tools predicting it to be damaging to protein function. Interestingly, the variant was present in both twins but was classified differently by each company: likely benign for Twin A (and therefore not reported) and VUS for Twin B. First degree relatives are advised to undergo clinical screening and cascade genetic testing for DSP p.R1002W. Discussion: The presentation described is consistent with arrhythmogenic cardiomyopathy (ACM) and the family history strongly supports a genetic etiology. DSP is a causal gene for ACM with unique clinical features that are strikingly similar to those observed herein. The differences in genes tested and variant adjudication between companies has left diagnostic uncertainty; hence, definitive pathogenicity cannot be attributed to either variant without cosegregation analysis, which is ongoing. In summary, this case illustrates the challenges of variant interpretation, and the impact that this can have on genetic counseling and family screening.