Submission Details

DSP was originally evaluated for DCM by the ClinGen DCM GCEP on 6/10/2020, and received the designation of “strong” evidence for DCM, after previous 2019 curation of “definitive” evidence for ARVC curated and published by the ARVC GCEP. Evidence of this gene in association with DCM, as defined by the DCM GCEP, was re-evaluated using SOP v10 on 3/5/2025.

The following evidence was originally curated by the ARVC GCEP to provide a Definitive Evidence classification of DSP with the arrthmogenic cardiomyopathy with woolly hair and keratoderma disease association: The DSP gene was the first ARVC-gene to be associated to the disease, the initial mutation description was done in Carvajal syndrome characterized by woolly hair, keratoderma and ARVC, it is transmitted in a autosomal recessive pattern, homozygous mutations in DSP were described in in the year 2000, PMID 11063735. This was followed by the description of a heterozygous mutation in DSP in an Italian family with ARVC and clear co-segregation of the variant with the disease, PMID 12373648. These findings have been replicated worldwide in several studies performed in different ethnicities, PMID 15941723, PMID 25765472, PMID 23954618, PMID 20864495, PMID 21397041, PMID 24938629. The initial descriptions recognized also a high frequency of left ventricular compromise in families with DSP mutations, PMID 16061754, PMID 28527814. A murine model was generated able to replicate the arrhythmia phenotype and Cx43 mislocalization, PMID 22240500. A transgenic mouse overexpressing a mutant DSP had increased cardiomyocyte apoptosis, cardiac fibrosis and lipid accumulation PMID 16917092. Abnormal DSP protein expression in DSP mutation carriers has also been reported, PMID 23137101. The role of this gene in this particular disease has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time (in general, at least 3 years). No convincing evidence has emerged that contradicts the role of the gene in the specified disease. In summary, based on this overwhelming evidence, DSP is definitely associated with arrhythmogenic cardiomyopathy with woolly hair and keratoderma, maximum association score was achieved rapidly after the analysis of few main reports.

It is clear with extensive interim publications that pathogenic variants in DSP present in a unique form that is an intermediate phenotype between DCM and ARVC and has been described with this unique MONDO ID 005021: arrhythmogenic cardiomyopathy with wooly hair and keratoderma. Pertinent to the DCM GCEP SOP v10, all cases of DCM with DSP variants have greater than expected arrhythmia burden, and families segregating DSP variants have mixed pedigrees with ARVC/DCM presentation. Therefore, this unique MONDO ID is most applicable. This recuration has provided repeated evidence over time that pathogenic DSP variants are associated with this unique phenotype, therefore, the DCM GCEP would add it’s support to also curating DSP as “definitive” for arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

In summary, DSP has continued to demonstrate definitive evidence to be associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma. Therefore, the DCM GCEP and the ARVC GCEP have collaboratively approved this classification as “Definitive” for this unique phenotype. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 31, 2025 (SOP Version 10).

The following PMIDs contributed to this evaluation: 39288222, 39011630, 38938828, 39742986, 38206263, 34352074, 39523938, 38860409, 38827944, 38383124, 38057295, 37830983, 37781308, 37008330, 36768812, 36580316, 36434384, 36231013, 35470109, 35083019, 34352074, 34343150, 33197325, 32372669