Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia and Loeys-Dietz Syndrome via the TGFB3 Gene

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a disease of the heart muscle primarily affecting the right ventricle. It is characterized by myocardial atrophy, fibrofatty replacement of the ventricular myocardium and inflammatory infiltrates. With disease progression and occasional left ventricle involvement, heart failure may result. The most common symptoms include ventricular arrhythmias, recurrent syncope, seizures and sudden death after physical or emotional stress. ARVC/D is present in ~20% of young sudden cardiac death victims (Corrado et al. 1998) and affects between 1/1000 and 1/5000 people worldwide with a higher prevalence in men than women (Corrado and Thiene 2006).

Loeys-Dietz syndrome (LDS) is characterized by two major clinical features: vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). Additional variable features include craniofacial abnormalities (ocular hypertelorism, bifid uvula/cleft palate and craniosynostosis) and cutaneous findings (translucent skin, easy bruising and dystrophic scars) (Loeys et al. 2005. PubMed ID: 15731757). Two clinical entities of LDS have been described (types 1 and 2), which represent a continuum of clinical features. Approximately 75% of patients with LDS type 1 have craniofacial manifestations, while approximately 25% of patients with LDS type 2 have cutaneous manifestations (Loeys et al. 2005. PubMed ID: 15731757; Loeys et al. 2006. PubMed ID: 16928994). LDS is usually characterized by aggressive arterial aneurysms (mean age at death is 26.1 years) and high incidence of pregnancy-related complications including death and uterine rupture (Loeys et al. 2005. PubMed ID: 15731757). Clinical features of LDS overlap with Marfan syndrome (Loeys et al. 2005. PubMed ID: 15731757; Loeys and Dietz. 2013. PubMed ID: 20301312).

ARVC/D is a heterogeneous disease that is inherited in about 50% of cases (Basso et al. 2004). Arrhythmogenic right ventricular dysplasia 1 is caused by pathogenic variants in TGFB3, and is inherited in an autosomal dominant pattern with age- and gender-dependent penetrance (Moric-Janiszewska et al. 2007). The transforming growth factor beta-3 encoded by TGFB3 is a member of the Transforming growth factor beta superfamily, which is involved in cell differentiation, embryogenesis and development. TGFB3 also plays critical roles in modulating cell adhesion and extracellular matrix formation (Kaartinen et al. 1995; Massagué et al. 2012). The TGFB3 gene contains 7 coding exons, encodes 412 amino acids and is located at 14q24.3. Most reported pathogenic variants in TGFB3 are missense or nonsense. No large deletions or duplications have been reported (Human Gene Mutation Database).

LDS is inherited in an autosomal dominant manner due to pathogenic variants in TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3 (Loeys et al. 2005. PubMed ID: 15731757; Mizuguchi et al. 2004. PubMed ID: 15235604; Rienhoff et al. 2013. PubMed ID: 23824657). TGFBR1, TGFBR2, SMAD3, and TGFB2 are all involved in TGFβ signaling. TGFB2 and TGFB3 are cytokines, TGFBR1 and TGFBR2 are receptors and SMAD3 is a signal transducer and transcription factor. A combination of truncating variants (nonsense, frameshifts) and missense variants have been found in TGFB3 (Rienhoff et al. 2013. PubMed ID: 23824657; Schepers et al. 2018. PubMed ID: 29392890). Approximately 25% of LDS cases are familial and 75% of cases are de novo (Loeys and Dietz. 2013. PubMed ID: 20301312).

PKP2, DSP, and DSG2, account for the great majority of known genetic causes of Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (McNally et al. 2014). TGFB3 is a relatively rare cause of ARVC/D. In one ARVCD genotype-phenotype study based on an Asian population, only 1 of 53 pathogenic variants occurred in TGFB3 (Bao et al. 2013).

Approximately 95% of Loeys-Dietz cases are found to have a pathogenic variant in TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3 (Loeys and Dietz. 2013. PubMed ID: 20301312). Approximately 1-5% of cases have a pathogenic variant in TGFB2 (Loeys and Dietz. 2013. PubMed ID: 20301312).

No large deletions or duplications have been reported in TGFB3 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TGFB3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.