Autosomal Dominant Progressive External Ophthalmoplegia via the DNA2 Gene

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder characterized by progressive external ophthalmoplegia and ptosis, with multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle (Chinnery 2014; Ronchi et al. 2013).

DNA2-related adPEO is characterized by progressive myopathy with muscle mitochondrial dysfunction (Ronchi et al. 2013). To date, only a few DNA2-linked adPEO patients have been reported (Ronchi et al. 2013). In these individuals, the disease was generally adult-onset, and patients presented with adPEO in combination with limb-girdle muscle weakness, predominantly in the lower limbs.

DNA2 defects represent a rare cause of autosomal dominant PEO (Ronchi et al. 2013). DNA2 has 21 coding exons that encode a helicase/nuclease family member involved in mtDNA replication and the long-patch base-excision repair (LP-BER) pathway (Copeland and Longley 2008; Zheng et al. 2008). The majority of reported pathogenic variants in DNA2 are missense changes (Human Gene Mutation Database).

Defects in C10orf2, POLG, POLG2, RRM2B, and SLC25A4 may also cause adPEO (Fratter et al. 2010).

In one cohort, three of 90 patients (3.3%) with multiple mtDNA deletions harbored pathogenic variants in the DNA2 gene (Ronchi et al. 2013).

No gross deletions or insertions have been reported in the DNA2 gene to date (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the DNA2 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).