Mitochondrial Membrane Protein-Associated Neurodegeneration via the C19orf12 Gene

Mitochondrial membrane Protein-Associated Neurodegeneration (MPAN) is the third common type of Neurodegeneration with Brain Iron Accumulation (NBIA). It has childhood onset, but occurs across all age groups. The manifestations include cognitive decline, progressive dementia, prominent neuropsychiatric abnormalities, motor neuronopathy, spasticity, dysarthria, dystonia, Parkinsonism and optic atrophy. Brain MRI shows iron accumulation in both globus pallidus and substantia nigra. Cortical and cerebellar atrophy are also common (Hogarth  et al. 2013; Arber et al 2016).

Mitochondrial membrane Protein-Associated Neurodegeneration is inherited in an autosomal recessive manner and is caused by pathogenic variants in the C19orf12 gene. The protein C19orf12 is located on the outer mitochondrial membrane with unclear function (Venco et al. 2015). Pathogenic variants in C19orf12 include missense, nonsense, small deletion and insertion, and splice variants (Hogarth et al. 2013; Tschentscher  et al. 2015; Human Gene Mutation Database). No large deletions or duplications have been reported to be causative for MPAN.

It has been estimated that pathogenic variants in C19orf12 account for 6-10% of neurodegeneration with brain iron accumulation (NBIA) (Arber et al. 2016).

This test provides full coverage of all coding exons of the C19orf12 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).