Autosomal Dominant Progressive External Ophthalmoplegia and other C10orf2-Related Disorders via the TWNK/C10orf2 Gene

Autosomal dominant progressive external ophthalmoplegia (adPEO) is one of several possible clinical manifestations of the mitochondrial DNA (mtDNA) deletion disorders. In TWNK/C10orf2-related adPEO, affected individuals display cytochrome c oxidase (COX)-deficient muscle fibers and multiple mtDNA deletions in skeletal muscle. The primary features of this disease are progressive external ophthalmoplegia (PEO) and ptosis, while other symptoms may include proximal muscle weakness, exercise intolerance, peripheral neuropathy, ataxia, cataracts, cardiomyopathy, and depression (Spelbrink et al. 2001). The sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) phenotype has also been reported (Hudson et al. 2005). In a group of adPEO patients from the United Kingdom and Germany, the mean age at onset was 42 years (range: 8-65 years) (Fratter et al. 2010).

Pathogenic variants in TWNK may also cause recessive, early-onset diseases of mtDNA maintenance, which include infantile-onset spinocerebellar ataxia (IOSCA) and the hepatocerebral form of mtDNA depletion syndrome (MDS) (Fratter et al. 2010).

IOSCA is a severe neurodegenerative disorder. Children with IOSCA typically develop progressive atrophy of the cerebellum, brain stem and spinal cord, in addition to sensory axonal neuropathy (Nikali et al. 2005). After normal development in the first year, children with IOSCA start to develop the following clinical features in successive order: spinocerebellar ataxia, muscle hypotonia, athetoid movements, loss of deep-tendon reflexes, hearing deficiency, ophthalmoplegia, optic atrophy, epileptic encephalopathy, and female primary hypergonadotropic hypogonadism (Koskinen et al. 1994; Koskinen et al. 1994; Nikali et al. 2010).

MDS is a group of clinically and genetically heterogeneous diseases characterized by a quantitative abnormality of the mitochondrial genome (Suomalainen and Isohanni, 2010; El-Hattab and Scaglia, 2013). The hepatocerebral form of MDS commonly presents with severe hepatopathy, hypotonia, and psychomotor delay. Clinical features may also include lactic acidosis, peripheral neuropathy, epilepsy, ophthalmoplegia, nystagmus, athetosis, ataxia, sensorineural hearing impairment, and cerebellar cortical atrophy. The TWNK-related hepatocerebral form of MDS has an early disease onset that presents during the neonatal or infantile periods.

Finally, pathogenic variants in TWNK have been reported as a rare cause of autosomal recessive Perrault syndrome (Morino et al. 2014). Perrault syndrome is a neurological disorder primarily characterized by gonadal dysgenesis in females and sensorineural hearing loss in both males and females. Additionally, affected individuals may present with ataxia, muscle weakness, ophthalmoplegia, nystagmus, and intellectual disability. To date, only four affected females from two unrelated families have been identified with TWNK-related Perrault syndrome (Morino et al. 2014). Sensorineural hearing loss was diagnosed during childhood in each case. At puberty, affected individuals presented with primary amenorrhea, a failure to develop secondary sexual characteristics, and gonadal dysfunction.

The TWNK gene is commonly known as TWINKLE, PEO or PEO1 in the literature. Pathogenic variants in the TWNK gene are the primary known cause of autosomal dominant progressive external ophthalmoplegia (adPEO) (Fratter et al. 2010). TWNK has 5 exons and encodes for a hexameric DNA helicase that assists with mtDNA replication. The majority of TWNK pathogenic variants are missense changes, although at least one small deletion and one large duplication have been reported to date. Most causative TWNK variants are clustered within exon 1 and 2 of the gene, and several de novo pathogenic variants have been reported (Fratter et al. 2010). Pathogenic variants in POLG, SLC25A4, POLG2, RRM2B, and DNA2 can also cause adPEO (Fratter et al. 2010; Ronchi et al. 2013).

Infantile-onset spinocerebellar ataxia (IOSCA) is an autosomal recessive disorder, and pathogenic variants in TWNK are the only identified cause of IOSCA (Nikali et al. 2010). For this disorder, only missense changes and one splicing variant have been reported to date. A major cause of IOSCA is the Finnish founder variant c.1523A>G (p.Tyr508Cys) in exon 3 (Nikali et al. 2005).

The hepatocerebral form of mtDNA depletion syndrome (MDS) is another TWNK-related autosomal recessive disorder. Pathogenic TWNK missense changes have been reported in several unrelated families with the hepatocerebral form of MDS (Sarzi et al. 2007; Hakonen et al. 2007). The POLG, DGUOK, and MPV17 genes are also associated with the hepatocerebral form of this disease (Suomalainen and Isohanni 2010; El-Hattab and Scaglia 2013).

Only two families have been described with TWNK-related autosomal recessive Perrault syndrome to date; in both families, missense changes were identified as causative for disease in affected individuals (Morino et al. 2014). Pathogenic variants in HSD17B4, HARS2, LARS2, and CLPP may also result in Perrault syndrome.

Currently, pathogenic variants in TWNK are the only identified cause of IOSCA, and all individuals diagnosed with IOSCA harbored two pathogenic variants in TWNK (Nikali et al. 2005). As a consequence, clinical sensitivity is expected to be high when detecting TWNK defects in patients with this disease. A TWNK defect is also likely in adPEO patients (Fratter et al. 2010). Out of 32 adPEO families, Fratter et al. identified 26 families with pathogenic variants in TWNK (~81%), while the remaining 6 families had defects in either POLG or SLC25A4. TWNK-associated mtDNA depletion syndrome has been reported in only five individuals to date, and is likely a rare cause of this disease (Sarzi et al. 2007; Hakonen et al. 2007). Additionally, TWNK defects are an infrequent cause of Perrault syndrome, as only four affected individuals have been described in the literature (Morino et al. 2004).

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