Infantile Cerebellar-Retinal Degeneration the ACO2 Gene

Infantile cerebellar-retinal degeneration (ICRD) is an autosomal recessive, severe, infantile-onset (2–6 months of age), neurodegenerative disorder characterized by variable appearance of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities (strabismus, nystagmus, abnormal eye movements). Affected individuals show profound psychomotor retardation and failure to acquire developmental milestones. Typical features include the appearance of head bobbing and athetoid movements of the upper limbs along with horizontal nystagmus (when the individuals were held at the upright position), gradual evolution of bilateral optic atrophy and steadily declining auditory brain response, reflecting sensorineural hearing loss of variable severity (Spiegel et al. 2012).

Combining homozygosity mapping with whole-exome sequencing enabled the identification of the c.336C>G (p.Ser112Arg) causative mutation in ACO2 in eight ICRD affected individuals. So far, only this mutation has been reported to be associated with ICRD (Human Gene Mutation Database). Also, c.336C>G is reported as a founder mutation in people of Arab ancestry because all eight affected individuals from two unrelated clans were homozygous for the mutation. Their parents (10 individuals) and one of the healthy sibs were heterozygous for this mutation, and three healthy sibs were homozygous for the normal allele. All affected individuals shared a similar homozygous haplotype, and this mutation was not found in 128 anonymous individuals of the same ethnic origin (Spiegel et al. 2012).

ACO2 encodes an essential mitochondrial metabolic enzyme aconitase a component of the Krebs cycle, which is known to be a crucial metabolic pathway that contributes to ATP synthesis. Cellular aconitase activity, measured in lymphoblasts of two ICRD affected individuals  showed severe reduction (Spiegel et al. 2012).

Predicting clinical sensitivity for the ACO2 gene is challenging due to genetic heterogeneity of optic atrophy. However, all the reported causative mutations are detectable by this method. Gross deletions have not been reported in this gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ACO2 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).