Naxos Disease and Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia via the JUP Gene

Palmoplantar Keratoderma with Arrhythmogenic Right Ventricular Cardiomyopathy and Woolly Hair, also known as Naxos disease, is a cardiocutaneous syndrome characterized by non-epidermolytic palmoplantar keratosis, woolly hair, and the typical cardiac features of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Usual symptoms include diffuse palmar and plantar keratosis, dense dull, bristly scalp hair, recurrent tachycardia, and palpitation. Additional symptoms include short fingers, curved nails, small hands and arms, atrial fibrillation, collapse and syncope. Naxos disease was first reported in patients from the Greek island Naxos (Protonotarios et al. Br Heart J 56:321-326, 1986). The cutaneous symptoms begin in early infancy, while the cardiac symptoms are manifested during puberty, often with syncope. Sudden death occurs in approximately 2% of patients (Protonotarios J Am Coll Cardiol 38:1477-1484, 2001). Naxos disease affects ~ 1/1000 people in the Greek islands (Protonotarios and Tsatsopoulou Cardiovasc Pathol 13:185-194, 2004).

Naxos disease is inherited in an autosomal recessive manner. In patients of Greek origin, Naxos disease is caused by a homozygous 2 bp-deletion in the JUP gene. This deletion is defined as c.2157delTG, and causes a frameshift leading to premature protein termination (McKoy et al. Lancet 355:2119-2124, 2000). Over 90% of homozygous individuals for the c.2157delTG have electrocardiographic abnormalities; while only minor ECG changes were detected in 25% of heterozygous carriers, who are clinically unaffected (Protonotarios J Am Coll Cardiol 38:1477-1484, 2001). The 2 bp-deletion was also reported in Naxos patients of Turkish origin. Naxos disease is genetically heterogeneous, as suggested by the absence of JUP mutations in Arab families (Djabali et al. J Invest Dermatol 118:557-560, 2002). In addition to Naxos disease, heterozygous mutations in JUP are associated with autosomal dominant AVRC/D without any cutaneous abnormality (Asimaki et al. Am J Hum Genet 81:964-973, 2007; Christensen et al. J Med Genet 47:736-744, 2010).

The JUP gene encodes junction plakoglobin, an important element of cell-cell adhesion complexes.

Sequencing of exon 12 is expected to detect mutations in all Naxos patients of Greek origin (McKoy et al. Lancet 355: 2119-2124, 2000).

This test provides full coverage of all coding exons of the JUP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).