Left Ventricular Noncompaction (LVNC) via the DTNA Gene

Left Ventricular Noncompaction (LVNC) cardiomyopathy is a heart condition believed to result from an arrest in cardiac development during embryogenesis, resulting in a spongy, noncompacted appearance. The numerous trabeculations are most pronounced in the left ventricle (Chin et al. 1990). Diagnosis is based on structural features using echocardiography and cardiac MRI. LVNC can occur in isolation or be found with other heart defects (most commonly dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or congenital heart defects), genetic syndromes (such as Barth syndrome), and neuromuscular disorders (Pignatelli et al. 2003; Wald et al 2004; Oechslin et al. 2011; Jefferies 2013). Prevalance of LVNC is estimated to be ~0.25% of adults referred for echocardiography (Sandhu et al. 2008). Eighteen to fifty percent of isolated LVNC cases in adults are believed to be familial (Hoedemaekers et al. 2010).

LVNC is a genetically heterogeneous disorder that is inherited in an autosomal dominant (ACTC1, DTNA, LDB3, LMNA, MYBPC3, MYH7, TNNT2, VCL) or X-linked recessive (TAFAZZIN) manner (Ichida et al 2001; Vatta et al. 2003; Hermida-Prieto et al. 2004; Klaassen et al. 2008; Hoedemaekers et al. 2010). Pathogenic variants in TAFAZZIN cause Barth syndrome, which can have LVNC as one of the symptoms. See individual gene test descriptions for information on molecular biology of gene products.

DTNA contains 743 amino acids, spans over 180 kb and is located at 18q12 (Sadoulet-Puccio et al. 1997). The α-dystrobrevin protein encoded by DTNA gene is part of the dystrophin-associated protein complex (DPC). DPC can be divided into 3 subcomplexes: the dystroglycan complex, the sarcoglycan complex, and the cytoplasmic complex (the syntrophins and dystrobrevin), which is responsible for connecting the actin cytoskeleton with extracellular matrix (chen et al. 1999). Pathogenic variants in DTNA gene could disrupt signal transduction pathways ( such as, TGF-β pathway, nitric oxide pathway), leading to developmental errors in the heart (Ichida et al. 2001). One missense pathogenic variant has been reported in DTNA for LVNC (Human Gene Mutation Database).

Only a limited number of cases associated with DTNA pathogenic variants have been reported. The clinical sensitivity for DTNA gene alone is not available yet. No large deletions or duplications in DTNA have been documented.

This test provides full coverage of all coding exons of the DTNA 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).