High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation

Cardiomyopathies might lead to end-stage heart disease with the requirement of drastic treatments like bridging up to transplant or heart transplantation. A not precisely known proportion of these diseases are genetically determined. We genotyped 43 index-patients (30 DCM, 10 ARVC, 3 RCM) with advanced or end stage cardiomyopathy using a gene panel which covered 46 known cardiomyopathy disease genes. Fifty-three variants with possible impact on disease in 33 patients were identified. Of these 27 (51%) were classified as likely pathogenic or pathogenic in the MYH7, MYL2, MYL3, NEXN, TNNC1, TNNI3, DES, LMNA, PKP2, PLN, RBM20, TTN, and CRYAB genes. Fifty-six percent (n = 24) of index-patients carried a likely pathogenic or pathogenic mutation. Of these 75% (n = 18) were familial and 25% (n = 6) sporadic cases. However, severe cardiomyopathy seemed to be not characterized by a specific mutation profile. Remarkably, we identified a novel homozygous PKP2-missense variant in a large consanguineous family with sudden death in early childhood and several members with heart transplantation in adolescent age

Compound Heterozygous FKTN Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant α-Dystroglycan Pattern

Fukutin encoded by FKTN is a ribitol 5-phosphate transferase involved in glycosylation of α-dystroglycan. It is known that mutations in FKTN affect the glycosylation of α-dystroglycan, leading to a dystroglycanopathy. Dystroglycanopathies are a group of syndromes with a broad clinical spectrum including dilated cardiomyopathy and muscular dystrophy. In this study, we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in FKTN. Our work showed that compound heterozygous mutations in FKTN lead to a loss of fully glycosylated α-dystroglycan and result in cardiomyopathy and end-stage heart failure at a young age

Clinical, familial and genetic data of 50 patients with advanced or end stage cardiomyopathy.

<p>Clinical, familial and genetic data of 50 patients with advanced or end stage cardiomyopathy.</p

Compound heterozygous FKTN\it FKTN variants in a patient with dilated cardiomyopathy led to an aberrant α\alpha-dystroglycan pattern

Fukutin encoded by $\it FKTN$ is a ribitol 5-phosphate transferase involved in glycosylation of $\alpha$-dystroglycan. It is known that mutations in $\it FKTN$ affect the glycosylation of $\alpha$-dystroglycan, leading to a dystroglycanopathy. Dystroglycanopathies are a group of syndromes with a broad clinical spectrum including dilated cardiomyopathy and muscular dystrophy. In this study, we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in $\it FKTN$. Our work showed that compound heterozygous mutations in $\it FKTN$ lead to a loss of fully glycosylated $\alpha$-dystroglycan and result in cardiomyopathy and end-stage heart failure at a young age

Pedigree of DCM-23 family and PKP2 c.2035C>T co-segregation.

<p><b>A.</b> Family members with HTx were homozygous carriers of <i>PKP2</i> c.2035C>T, p.His679Tyr whereas heterozygous carriers and the homozygous carrier III/11 had no signs of cardiomyopathy. The <i>LAMA4</i> variant did not co-segregate with disease (data not shown). Squares = males, circles = females. Deceased individuals are indicated by slashes. Filled symbols indicate individuals with DCM. The index-patient is marked with an arrow. Genotypes are shown by present (+) or by absent (-) of the gene variant. <b>Abbreviations</b>: <b>SCD</b> = sudden cardiac death, <b>SID</b> = sudden infant death, <b>SUD</b> = unexplained sudden death. <b>B.</b> Haplotype analyses of <i>PKP2</i> c.2035C>T mutation carriers from family DCM-23. Haplotypes associated with the <i>PKP2</i> mutation are shown in grey shaded areas. These haplotypes are identical in both parents (II/8, II/9) with the exception of marker D12S61. Abbreviation: <b>cM</b> = centimorgan.</p

Variant carrying genes.

<p>In DCM-cases <i>TTN</i> carried the most variants. Of 19 <i>TTN</i>-variants in DCM-cases, 6 were truncating variants. The other affected genes were <i>TNNT2</i>, <i>TNNC1</i>, <i>RBM20</i>, <i>PKP2</i>, <i>NEXN</i>, <i>MYL2</i>, <i>MYH7</i>, <i>LMNA</i>, <i>DSP</i>, and <i>DES</i>. In ARVC-cases predominantly <i>PKP2</i>- and <i>TTN</i>-variants were identified. Further variants were found in the genes <i>PRKAG2</i>, <i>PLN</i>, <i>MYH7</i>, <i>MYH6</i>, <i>LMNA</i>, and <i>DES</i>. In the cohort of the RCM-cases variants in 3 different genes were identified: <i>TNNI3</i>, <i>MYL3</i>, and <i>CRYAB</i>. ACMG class 3–5 <i>=</i> variant of uncertain significance, likely pathogenic, pathogenic, respectively.</p

Distribution of variant classes.

<p>We genotyped 43 index-patients. Of these 18 familial and 6 sporadic cases carried (likely) pathogenic mutations. At least variants of uncertain significance were found in 4 familial and 5 sporadic cases. Only likely benign variants or variants with an allele frequency exceeding the disease prevalence were identified in 10 patients (6 familial, 4 sporadic cases). Familial disposition for the cardiomyopathy is based on pedigree analysis and family reports. <b>Abbreviations: F</b> = familial cases, <b>no label</b> = sporadic cases.</p

Clinical, familial and genetic data of 50 patients with advanced or end stage cardiomyopathy.

<p>Clinical, familial and genetic data of 50 patients with advanced or end stage cardiomyopathy.</p

Classification of the variants.

<p>In 60% of DCM- and 40% of ARVC-cases pathogenic and/or likely pathogenic mutations were identified. At least variants with uncertain significance were found in 17% DCM- and 30% ARVC-cases. No relevant variants (MAF >0.0005 in etiological matching controls) were found in 22% and 30% of DCM-, and ARVC-cases, respectively. In RCM-cases, 2 pathogenic and/or likely pathogenic mutations and 1 variant with uncertain significance were identified. <b>Abbreviations</b>: <b>class 2</b> = likely benign, c<b>lass 3</b> = variant of uncertain significance, <b>class 4</b> = likely pathogenic, <b>class 5</b> = pathogenic.</p