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<p>Arrhythmogenic right ventricular cardiomyopathy (ARVC; OMIM #609040) is an inherited cardiomyopathy characterized by juvenile sudden cardiac death (SCD), with &gt; 40% of familial cases driven by PLAKOPHILIN 2 (<i>PKP2</i>; OMIM #602861) mutations. This study reports a Chinese ARVC family with neonatal severe early-onset phenotype caused by novel compound heterozygous <i>PKP2</i> mutations that exhibiting cosegregation with biallelic mutations (while heterozygous carriers remained asymptomatic), and aims to elucidate the synergistic pathogenic mechanisms and clinical implications.&#xa0;Mutations were identified via whole-genome sequencing and familial cosegregation analysis. Pathogenicity was predicted using SpliceAI and MutationTaster. MiniGene splicing assays and RT-PCR validated aberrant splicing. We analyzed subcellular protein localization by immunofluorescence microscopy and assessed protein stability via cycloheximide chase (CHX).&#xa0;The proband carried a maternally inherited novel splice-site variant (<i>PKP2</i>: c.224–3&#xa0;C &gt; G) and a paternally inherited frameshift deletion (<i>PKP2</i>: c.1125_1132del). Functional validation demonstrated: (a) c.224–3&#xa0;C &gt; G caused exon 2 skipping (deletion rate &gt; 90%), generating a truncated protein (p.Asn76Trpfs*7); (b) c.1125_1132del induced frameshift (p.Phe376Alafs*8) without altering splicing. The mutant protein exhibited unchanged half-life but aberrant nuclear aggregation (immunofluorescence-confirmed).&#xa0;This study first confirms that compound heterozygous <i>PKP2</i> mutations cause severe early-onset ARVC through biallelic inactivation: the maternal splice variant (c.224–3&#xa0;C &gt; G) truncates the protein, ablating all functional domains, while the paternal frameshift mutation (c.1125_1132del) mislocalizes the protein to the nucleus. Both defects synergistically disrupt desmosomal integrity in cardiomyocytes. These findings expand the <i>PKP2</i>-associated genotype-phenotype spectrum and provide molecular basis for prenatal diagnosis and genetic counseling in high-risk families.</p>

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Novel PKP2 compound heterozygous mutations causing neonatal early-onset arrhythmogenic cardiomyopathy: insights into the synergistic pathogenicity of biallelic inactivation

  • 期刊论文

  • 发表日期：

    2026年1月15日

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  • Xiaobin Li,
  • Wenjun Yu,
  • Xiaolong Yuan,
  • Zhengke Li,
  • Runlin Leng,
  • Xiang Gao,
  • Guohua Yang

摘要

Arrhythmogenic right ventricular cardiomyopathy (ARVC; OMIM #609040) is an inherited cardiomyopathy characterized by juvenile sudden cardiac death (SCD), with > 40% of familial cases driven by PLAKOPHILIN 2 (PKP2; OMIM #602861) mutations. This study reports a Chinese ARVC family with neonatal severe early-onset phenotype caused by novel compound heterozygous PKP2 mutations that exhibiting cosegregation with biallelic mutations (while heterozygous carriers remained asymptomatic), and aims to elucidate the synergistic pathogenic mechanisms and clinical implications. Mutations were identified via whole-genome sequencing and familial cosegregation analysis. Pathogenicity was predicted using SpliceAI and MutationTaster. MiniGene splicing assays and RT-PCR validated aberrant splicing. We analyzed subcellular protein localization by immunofluorescence microscopy and assessed protein stability via cycloheximide chase (CHX). The proband carried a maternally inherited novel splice-site variant (PKP2: c.224–3 C > G) and a paternally inherited frameshift deletion (PKP2: c.1125_1132del). Functional validation demonstrated: (a) c.224–3 C > G caused exon 2 skipping (deletion rate > 90%), generating a truncated protein (p.Asn76Trpfs*7); (b) c.1125_1132del induced frameshift (p.Phe376Alafs*8) without altering splicing. The mutant protein exhibited unchanged half-life but aberrant nuclear aggregation (immunofluorescence-confirmed). This study first confirms that compound heterozygous PKP2 mutations cause severe early-onset ARVC through biallelic inactivation: the maternal splice variant (c.224–3 C > G) truncates the protein, ablating all functional domains, while the paternal frameshift mutation (c.1125_1132del) mislocalizes the protein to the nucleus. Both defects synergistically disrupt desmosomal integrity in cardiomyocytes. These findings expand the PKP2-associated genotype-phenotype spectrum and provide molecular basis for prenatal diagnosis and genetic counseling in high-risk families.