The Genotype-Phenotype Puzzle of Desmoplakin Variants: CMR findings for Variants of Uncertain Significance

Presenting Author(s)

• 

  Margaux Everingham, MD

  Resident Physician
  University of Virginia Health System
  Charlottesville, Virginia, United States

Primary Author(s)

• 

  Margaux Everingham, MD

  Resident Physician
  University of Virginia Health System
  Charlottesville, Virginia, United States

Co-Author(s)

• CM

  Ceylan Metin

  Medical Student
  University of Virginia Health System, United States
• CD

  Cristiane C. De Carvalho Singulane, MD

  Postdoctoral Researcher
  University of Virginia Health System
  Charlottesville, Virginia, United States
• MT

  Matthew Thomas

  Genetic Counselor
  University of Virginia Health System, United States
• KA

  Kaitlyn Amos

  Genetic Counselor
  University of Virginia Health System, United States
• 

  Amit R. Patel, MD, FSCMR

  Professor of Medicine
  Division of Cardiology, University of Virginia Health System, Charlottesville, Virginia, USA.
  Charlottesville, Virginia, United States
• 

  Jonathan A. Pan, MD, MSc, MBA

  Assistant Professor
  University of Virginia Health System
  Charlottesville, Virginia, United States

Background: Pathogenic and likely pathogenic variants (P/LP) in desmoplakin (DSP) are known to cause extensive subepicardial late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR). There are numerous variants of uncertain significance (VUS) in DSP which may also demonstrate unique findings on CMR.

Methods: A series of patients with P/LP DSP variants and VUS aged ≥18 years was retrospectively identified. Clinical history, outcome data, and imaging studies were systematically collected from the electronic medical record. CMR with gadolinium contrast was performed and analyzed in accordance with SCMR guidelines. Genotype–phenotype associations were assessed using descriptive statistics. Differences in CMR parameters were assessed using an independent sample t-test. Significance was defined as p < 0.05.

Results: Of the 15 patients included in the study, 7 had P/LP mutations and 8 had VUS. All patients with P/LP variants had predicted loss-of-function mutations. Of the patients with VUS, 7 had missense variants and 1 had an intronic deletion. Patients in the P/LP and VUS cohorts were similar in their baseline characteristics. Patients in the P/LP cohort were more likely to have a family history of sudden cardiac death (SCD) than patients in the VUS cohort (n=2 vs n=0, respectively).



The average amount of LGE was higher in the P/LP cohort versus the VUS cohort, though the difference is not statistically significant (9.5 ± 11g and 1.7 ± 1.9g, respectively; p=0.081). In the P/LP cohort, 5 of the 7 patients had epicardial and subepicardial LGE. In the VUS cohort, 2 of the 8 patients had a small foci of LGE in nonspecific patterns and 2 other patients of the 8 demonstrated patchy subendocardial LGE. The left ventricular ejection fraction was significantly lower in the P/LP cohort versus the VUS cohort (40 ± 12% versus 52 ± 11%; p=0.045). The right ventricular ejection fraction was similar in both the P/LP and VUS cohort (45 ± 7% and 46 ± 6%, respectively; p=0.750).

Conclusion: In this case series, when compared to VUS, P/LP mutations were associated with higher LGE burden and reduced LV systolic function, but similar RV systolic function. Given the heterogeneity of CMR findings, genetic testing may be considered in patients with unexplained LV dysfunction and non-ischemic LGE. Further investigation is needed to better describe complex genotype phenotype relationships in DSP variants (both P/LP and VUS) and CMR findings.

Cardiac Magnetic Resonance Findings in P/LP Variants vs VUS

	P/LP (mean ± SD)	VUS (mean ± SD)
SAx LV EF (%)	40 ± 12	52 ± 11
SAx LV Mass Index (g/m²)	55 ± 9	65 ± 19
SAx LV EDVi (ml/m²)	118 ± 29	85 ± 36
SAx LV ESVi (ml/m²)	74 ± 32	43 ± 29
SAx RV EF (%)	45 ± 7	46 ± 6
SAx RV EDVi (ml/m²)	84 ± 15	81 ± 26
SAx RV ESVi (ml/m²)	46 ± 9	35 ± 25
Late Enhancement Percent	9.5 ± 11	1.7 ± 1.9

Cardiac Magnetic Resonance Findings in P/LP Variants vs VUS

	P/LP mean ± SD	VUS mean ± SD	P Value
LV EF (%)	40 ± 12	52 ± 11	0.045*
LV Mass Index (g/m²)	55 ± 9	65 ± 19	0.232
LV EDVi (ml/m²)	118 ± 29	85 ± 36	0.071
LV ESVi (ml/m²)	74 ± 32	43 ± 29	0.071
RV EF (%)	45 ± 7	46 ± 6	0.750
RV EDVi (ml/m²)	84 ± 15	81 ± 26	0.843
RV ESVi (ml/m²)	46 ± 9	35 ± 25	0.281
Late Enhancement (%)	9.5 ± 11	1.7 ± 1.9	0.081

Figure 2: Representative CMR with subepicardial LGE from cohort with pathogenic or likely pathogenic variants.
Figure 3: Representative CMR with patchy subendocardial LGE from cohort with variants of uncertain significance.