A case of ACM with cardiocutaneous manifestations associated with a novel homozygous DSC2 variant

Introduction: Homozygous pathogenic variants in the JUP and DSP genes have been associated with recessive forms of arrhythmogenic cardiomyopathy (ACM) and cardiocutaneous syndromes. We describe a case associated with a novel homozygous DSC2 variant.

Case Description: We report the case of a 37 year old male from Turkiye presenting with repeated syncope and palpitations. Physical examination was normal. Family history was stated to be negative for sudden cardiac death or other heart disease. A syncope experienced during Holter monitoring correlated with an episode of non-sustained ventricular tachycardia (Figure 1A). T-wave inversions in V4-6 were noted in his ECG (Figure 1B). An echocardiogram was performed which showed signs of RV dysfunction. Further evaluation by cardiac MRI revealed a RV ejection fraction of 22% and an indexed RV enddiastolic volume of 118 ml/m2 (Figure 1C). The MRI also showed LGE of the RV and LV apex. The patient was treated with beta blockers and received an ICD. A diagnosis of ACM was made since one major and two minor criteria were fulfilled. For further evaluation genetic testing was initiated. We identified a previously not described homozygous intronic variant in the DSC2 gene (NC_000018.10(NM_024422.6).354+3A>G) initially classified as a variant of uncertain significance (VUS) as well as a heterozygous DSP variant (NM_004515.4:c.6269A>G p.Glu2090Gly) also classified as VUS. We performed mRNA analysis revealing an effect of the DSC2 variant on splicing resulting in two different transcripts with premature translation stops in both (Figure 1D) and the loss of a functional protein. Thus, the DSC2 variant was reclassified as pathogenic. Upon reexamination, the patient showed signs of palmoplantar keratoderma and wooly hair which had been present since birth. In addition, family history was reevaluated and the patient reported that consanguinity was known in his family (Figure 1E). 

Discussion: The presented phenotype is associated with autosomal recessive forms of ACM such as Naxos disease and Carvajal syndrome caused by pathogenic variants in JUP and DSP, respectively. Our findings suggest, that the homozygous DSC2 variant we identified might represent a subtype of a cardiocutaneous syndrome. However, we cannot exclude a functional impact of the concomitant DSP variant which warrants further investigation.

Figure 1: A, Non-sustained VT detected on Holter monitoring. B, EKG showing T-wave inversions in V4-V6. C, Cardiac MRI showing dilated RV and LGE at the RV and LV apex. D, Prediction of DSC2 variant affecting splicing and sequence of the two resulting transcripts; transcript 1 missing exon 3 and transcript 2 including 37 intronic bases instead of exon 3, resulting in a non-functional protein. E, Pedigree showing several cases of consanguinity.