Homozygous Truncating Variant in
            <i>PKP2</i>
            Causes Hypoplastic Left Heart Syndrome

Verhagen, Judith M.A.; Born, Myrthe van den; Kurul, Şerife; Asimaki, Angeliki; Laar, Ingrid M.B.H. van de; Frohn-Mulder, Ingrid M.E.; Kammeraad, Janneke A.E.; Yap, Sing-Chien; Bartelings, Margot M.; Slegtenhorst, Marjon A. van; Thüsen, Jan H. von der; Wessels, Marja W.

doi:10.1161/circgen.118.002397

Cited by 11 publications

(9 citation statements)

References 4 publications

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“…The presence of loss of function PKP2 variants on each allele (homozygous or compound heterozygous null alleles) may be particularly devastating. There are multiple reports of infants/fetuses with congenital heart disease and poor neonatal outcomes with this genotype (40,41), consistent with the requirement of plakophilin-2 for cardiac development (42).…”

Section: Genotype-phenotype Associationssupporting

confidence: 58%

Arrhythmogenic Right Ventricular Cardiomyopathy in Pediatric Patients: An Important but Underrecognized Clinical Entity

et al. 2021

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular (RV) myocardium. Affected patients typically present as young adults with hemodynamically stable ventricular tachycardia, although pediatric cases are increasingly recognized. These young subjects often have a more severe phenotype with a high risk of sudden cardiac death (SCD) and progression toward heart failure. Diagnosis of ARVC is made by combining multiple sources of information as prescribed by the consensus-based Task Force Criteria. The description of Naxos disease, a fully penetrant autosomal recessive disorder that is associated with ARVC and a cutaneous phenotype of palmoplantar keratoderma and wooly hair facilitated the identification of the genetic cause of ARVC. At present, approximately 60% of patients are found to carry a pathogenic variant in one of five genes associated with the cardiac desmosome. The incomplete penetrance and variable expressivity of these variants however implies an important role for environmental factors, of which participation in endurance exercise is a strong risk factor. Since there currently is no definite cure for ARVC, disease management is directed toward symptom reduction, delay of disease progression, and prevention of SCD. This clinically focused review describes the spectrum of ARVC among children and adolescents, the genetic architecture underlying this disease, the cardio-cutaneous syndromes that led to its identification, and current diagnostic and therapeutic strategies in pediatric ARVC subjects.

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Section: Genotype-phenotype Associationssupporting

confidence: 58%

Arrhythmogenic Right Ventricular Cardiomyopathy in Pediatric Patients: An Important but Underrecognized Clinical Entity

et al. 2021

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“…Our findings are in agreement with the study in knock-out mice that homozygous null allele resulted in lethal cardiomyopathy, including reduced trabeculation of the ventricles, molecularly reduced architectural stability of the intercalated disks, disarrayed cytoskeleton, and ruptures of cardiac walls (20). Based on our review of the literature, there were only nine PKP2 variants present in biallelic mutations, seven of which were null variants, including small insertion/deletions (indels), wholegene deletion, and splicing defects (Table 1) (10)(11)(12)(13)(14)(15)(16). The null alleles were associated with severe lethal phenotypes, namely, hypoplastic left heart syndrome (HLHS) and ventricular noncompaction with perinatal onset of cardiac failure (families 1, 2, and 9).…”

Section: Discussionmentioning

confidence: 99%

“…We also reviewed previously reported biallelic mutations of PKP2, with just eight families described in the literature, as summarized in Table 1 (10)(11)(12)(13)(14)(15)(16).…”

Section: Genetic Datamentioning

confidence: 99%

A Novel Homozygous PKP2 Variant in Severe Neonatal Non-compaction and Concomitant Ventricular Septal Defect: A Case Report

2022

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Left ventricular non-compaction (LVNC) is a rare and genetically heterogeneous cardiomyopathy. The disorder vastly affects infants and young children. Severe neonatal LVNC is relatively rare. The prevalence of genetic defects underlying pediatric and adult-onset LVNC is about 17–40%. Mutations of MYH7 and MYBPC3 sarcomeric genes are found in the vast majority of the positive pediatric cases. PKP2 encodes plakophilin-2, a non-sarcomeric desmosomal protein, which has multiple roles in cardiac myocytes including cell–cell adhesion, tightening gap junction, and transcriptional factor. Most of the reported PKP2 mutations are heterozygous missense and truncating variants, and they are associated with an adult-onset autosomal dominant disorder, namely arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Homozygous PKP2 mutations have been rarely described. Herein, we present a rare case of an infant with neonatal onset of congestive heart failure owing to severe LVNC and multiple muscular VSD. Medical treatments failed to control the heart failure and the patient died at 11 months of age. Whole-exome sequencing identified a novel homozygous PKP2 variant, c.1511-1G>C, in the patient. An mRNA analysis revealed aberrant transcript lacking exon 7, which was predicted to cause a frameshift and truncated peptide (p.Gly460GlufsTer2). The heterozygous parents had normal cardiac structures and functions as demonstrated by electrocardiogram and echocardiography. Pathogenic variants of sarcomeric genes analyzed were not found in the patient. We conducted a literature review and identified eight families with biallelic PKP2 mutations. We observed that three families (our included) with null variants were linked to lethal phenotypes, while homozygous missense mutations resulted in less severe manifestations: adolescent-onset ARVD/C and childhood-onset DCM. Our data support a previous notion that severe neonatal LVNC might represent a unique entity and had distinct genetic spectrum. In conclusion, the present study has extended the phenotypes and genotypes of PKP2-related disorders and lethal LVNC.

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“…Also variants in transcription factor genes, such as GATA4 and TBX20, have been associated with both CHD and dilated cardiomyopathy (28)(29)(30). Recently, a homozygous truncating variant in PKP2, a gene previously associated with arrhythmogenic right ventricular cardiomyopathy, was evaluated as causal in two siblings diagnosed with severe HLHS with prominently trabeculated abnormal myocardium and reduced contractility of both ventricles (31).…”

Section: Discussionmentioning

confidence: 99%

Rare Variants in Genes Associated With Cardiomyopathy Are Not Common in Hypoplastic Left Heart Syndrome Patients With Myocardial Dysfunction

et al. 2020

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Myocardial dysfunction is a known risk factor for morbidity and mortality in hypoplastic left heart syndrome (HLHS). Variants in some transcription factor and contractility genes, which are known to cause cardiomyopathy, have previously been associated with impaired right ventricular function in some HLHS patients. The care of HLHS patients is resource demanding. Identifying genetic variants associated with myocardial dysfunction would be helpful in tailoring the follow-up and therapeutic strategies. We tested whether a commercial cardiomyopathy gene panel could serve as a diagnostic tool in a Finnish cohort of HLHS patients with impaired right ventricular function to identify potentially pathogenic variants associated with poor prognosis. None of the patients had pathogenic or likely pathogenic variants in the studied cardiomyopathy-associated genes. Thus, our approach of performing a cardiomyopathy gene panel to identify pathogenic variants as directly causal or as modifiers for worse outcomes in hypoplastic left heart syndrome is not useful in clinical practice at the moment.

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Homozygous Truncating Variant in PKP2 Causes Hypoplastic Left Heart Syndrome

Cited by 11 publications

References 4 publications

Arrhythmogenic Right Ventricular Cardiomyopathy in Pediatric Patients: An Important but Underrecognized Clinical Entity

Arrhythmogenic Right Ventricular Cardiomyopathy in Pediatric Patients: An Important but Underrecognized Clinical Entity

A Novel Homozygous PKP2 Variant in Severe Neonatal Non-compaction and Concomitant Ventricular Septal Defect: A Case Report

Rare Variants in Genes Associated With Cardiomyopathy Are Not Common in Hypoplastic Left Heart Syndrome Patients With Myocardial Dysfunction

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