Sengers Syndrome via the AGK Gene

Sengers syndrome is clinically characterized by exercise intolerance, hypertrophic cardiomyopathy, skeletal myopathy, and congenital cataracts (Mayr et al. 2012; Calvo et al. 2012). As a result of mitochondrial DNA (mtDNA) depletion in these individuals, patients also present with severe lactic acidemia and combined mitochondrial complex deficiencies (Calvo et al. 2012; Siriwardena et al. 2013).

This disorder can be separated into two distinct forms based on clinical onset. The most severe form of this disease, which typically occurs in neonates, is often fatal. In contrast, patients who present with Sengers syndrome in late infancy or childhood may survive for several decades following diagnosis (Mayr et al. 2012).

Autosomal recessive Sengers syndrome is caused by pathogenic variants in the AGK gene, which is located on chromosome 7q34 (Mayr et al. 2012). AGK encodes for a mitochondrial acylglycerol kinase that catalyzes the phosphorylation of diacylglycerol (DAG) and monoacylglycerol to phosphatidic acid (PA) and lysophosphatidic acid (LPA), respectively (Bektas et al. 2005). Although the precise molecular role of AGK in Sengers syndrome is still being explored, loss or inactivation of AGK may result in accumulation of cellular DAG, subsequently increasing downstream production of toxic free radicals and causing severe oxidative damage to mitochondria (Siriwardena et al. 2013). Additionally, decreases in cellular PA may also destabilize the assembly of the adenine nucleotide translocators (ANTs), a subset of highly abundant mitochondrial proteins essential for ADP/ATP translocation across the mitochondrial inner membrane (Mayr et al. 2012).

Approximately 20 different pathogenic variants have been documented for AGK-associated Sengers syndrome (Calvo et al. 2012; Mayr et al. 2012; Siriwardena et al. 2013). The majority of these variants result in premature protein truncation. However, missense variants, and at least one gross deletion have also been reported.

Too few cases of Sengers syndrome (~40) have been reported to precisely estimate clinical sensitivity. However, as AGK is the only gene that has been associated with this disorder, clinical sensitivity is expected to be high.

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