Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies

Abstract

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.

Keywords: arrhythmias; cardiomyopathies; genetic counseling; genetics; sudden cardiac death.

FIGURE 1

Electropherogram of pathogenic variants identified in our families and closest proteins interactions. (A) Families A and B: c.275T > A (TTG > TAG), p.L92X (p.Leu92^∗) in the PKP2 gene. Families C and D: c.1237C > T (CGA > TGA) and p.R413X (p.Arg413^∗) in the PKP2 gene. Families E and F: c.2670dupG, p.R891A_frX160 (p.Arg891Ala_fs^∗160) in the MYBPC3 gene. (B) Network of ten closest proteins to PKP2. (C) Network of ten closest proteins to MYBPC3.

FIGURE 2

Pedigree of family (A). Generations are indicated in the left side. Each individual is identified with a number. Clinically affected patients are show in gray, clinically unaffected patients are show in white, and slashes indicate a deceased relative. Index case is indicated with an arrow (III.1). The genetic carriers of PKP2_p.(Leu92^∗) are represented with a plus sign inside rounds/squares. Minus sign indicates non-carriers of the genetic variant. Question mark indicates no genetic analysis available. The ECG corresponds to index case. The ECG showing negative T waves in V1-3, and prolonged Terminal Activation Duration as major and respectively, minor diagnostic Task Force Criteria for ACM.

FIGURE 3

Pedigree of family B. Generations are indicated in the left side. Each individual is identified with a number. Clinically affected patients are shown in gray, clinically unaffected patients are shown in white, and slashes indicate a deceased relative. Index case is indicated with an arrow (III.1). The genetic carriers of PKP2_p.(Leu92^∗) are represented with a plus sign inside rounds/squares. Minus sign indicates non-carriers of the genetic variant. Question mark indicates no genetic analysis available. SD means Sudden Death. The ECG corresponds to index case. ECG showing negative T waves in V1-2 (minor ACM criterion).

FIGURE 4

Pedigree of family C. Generations are indicated in the left side. Each individual is identified with a number. Clinically affected patients are shown in gray, clinically unaffected patients are shown in white, and slashes indicate a deceased relative. Index case is indicated with an arrow (II.2). The genetic carriers of PKP2_p.(Arg413^∗) are represented with a plus sign inside rounds/squares. Minus sign indicates non-carriers of the genetic variant. Question mark indicates no genetic analysis available. SD means Sudden Death. The ECG corresponds to index case.

FIGURE 5

Pedigree of family D. Generations are indicated in the left side. Each individual is identified with a number. Clinically affected patients are shown in gray, clinically unaffected patients are shown in white, and slashes indicate a deceased relative. Index case is indicated with an arrow (IV.1). The genetic carriers of PKP2_p.(Arg413^∗) are represented with a plus sign inside rounds/squares. Minus sign indicates non-carriers of the genetic variant. Question mark indicates no genetic analysis available. SD means Sudden Death. The ECG corresponds to IV.1.

FIGURE 6

Pedigree of family E. Generations are indicated in the left side. Each individual is identified with a number. Clinically affected patients are shown in gray, clinically unaffected patients are shown in white, and slashes indicate a deceased relative. Index case is indicated with an arrow (III.2). The genetic carriers of MYBPC3_p.(Arg891Alafs^∗160) are represented with a plus sign inside rounds/squares. Minus sign indicates non-carriers of the genetic variant. Question mark indicates no genetic analysis available. SD means Sudden Death. The ECG corresponds to index case.

FIGURE 7

Pedigree of family F. Generations are indicated in the left side. Each individual is identified with a number. Clinically affected patients are shown in gray, clinically unaffected patients are shown in white, and slashes indicate a deceased relative. Index case is indicated with an arrow (II.2). The genetic carriers of MYBPC3_p.(Arg891Alafs^∗160) are represented with a plus sign inside rounds/squares. Minus sign indicates non-carriers of the genetic variant. Question mark indicates no genetic analysis available. The ECG corresponds to index case.