Dilated Cardiomyopathy via the ANKRD1 Gene

Dilated Cardiomyopathy (DCM) is a heterogeneous disease of the cardiac muscle. It is characterized by dilatation of the left, right, or both ventricles, systolic dysfunction, and diminished myocardial contractility. Symptoms include arrhythmia, dyspnea, chest pain, palpitation, fainting, and congestive heart failure (Ikram et al. 1987). Additional features may include conduction defects, woolly hair, and skeletal myopathy (Møller et al. 2009). Although symptoms of DCM usually begin in adulthood, an extensive clinical variability between individuals concerning the age of onset, penetrance, and extent of structural and functional abnormality has been documented. The prevalence of DCM has been estimated at ~1/2700 (Codd et al. 1989), but it could be 10-folder higher as proposed by another study (Hershberger et al. 2013).

Dilated Cardiomyopathy (DCM) is familial in 30%-50% of cases (de Gonzalo-Calvo et al. 2017). Pathogenic variants in ANKRD1 have been reported to be associated with Dilated Cardiomyopathy, and are inherited in an autosomal dominant pattern (limited cases) (Duboscq-Bidot et al. 2009; Moulik et al. 2009). Cardiac-specific stress-response protein (CARP) encoded by ANKRD1 belongs to the muscle ankyrin repeat protein (MARP) family. CARP interacts with N2A domain of titin and translocates into nucleus to regulate the transcription in response to a stretch as part of mechanical stretch-based signaling machinery in cardiac myocytes. Pathogenic variants in ANKRD1 alter the interaction between CARP and associated protein and impair the stretch based cellular pathway. CARP is up regulated in dilated cardiomyopathy in response to mechanical stress (Bogomolovas et al. 2015) The ANKRD1 gene contains 9 coding exons, encodes 319 amino acids and is located at 10q23.31. Most reported pathogenic variants in ANKRD1 are missense or nonsense (Human Gene Mutation Database).

Pathogenic variants in ANKRD1 were identified in ~2% of Dilated Cardiomyopathy cases (Moulik et al. 2009; Duboscq-Bidot et al. 2009).

This test provides full coverage of all coding exons of the ANKRD1 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).