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Combined Oxidative Phosphorylation Deficiency 14 via the FARS2 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
FARS2 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4151FARS281479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

Clinical Features

Combined oxidative phosphorylation deficiency 14 (COXPD14) is a multisystemic disorder caused by mitochondrial enzyme deficiency. COXPD14 presents in infancy as tonic or myoclonic seizures with eye involvement. The seizures may at first respond well to anti-epileptic drugs, but eventually become drug resistant. EEG may reveal hypsarrhythmia or multifocal spikes (Almalki et al. 2014). There is little to no psychomotor development in COXPD14 patients after 6 months of age. Initial MRI results may be normal, but as the disease progresses some combination of the following is seen: symmetrical subcortical white matter lesions, thinning of the corpus callosum, and cortical degeneration. Metabolic analysis revealed elevated blood lactate levels and muscle biopsy showed reduced cytochrome c oxidase (COX) staining (Elo et al. 2012; Shamseldin et al. 2012). Death typically occurs within the first three years of life.

Genetics

COXPD14 is inherited in an autosomal recessive manner and is caused by variants in the FARS2 gene. Pathogenic missense variants in the FARS2 gene have been reported in COXPD14 patients (Shamseldin et al. 2012; Elo et al. 2012; Almalki et al. 2014). The nuclear gene FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase, which attaches a phenylalanine to the cognate mitochondrial tRNA. In vitro studies of mutant FARS2 showed inability to bind ATP and loss of aminoacylation activity, suggesting missense variants lead to loss of FARS2 function (Elo et al. 2012). One study using patient derived cell lines only saw FARS2/mitochondrial defects in myoblasts and not fibroblasts. This is consistent with the higher energy demand of myoblasts and tendency of mitochondrial disorders to present as encephalomyopathies (Elo et al. 2012; Shamseldin et al. 2012). The 13 mitochondrial transcribed genes encode proteins that are part of the oxidative phosphorylation (OXPHOS) complex. It is hypothesized that inefficient translation of OXPHOS complex proteins due to FARS2 deficiency underlies the COXPD14 phenotype.

Clinical Sensitivity - Sequencing with CNV PG-Select

In one study of patients from consanguineous families with suspected mitochondrial energy disorders, homozygous pathogenic variants in FARS2 were identified in 1 of 13 families (Shamseldin et al. 2012).

Testing Strategy

This test provides full coverage of all coding exons of the FARS2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

FARS2 sequencing should be considered in patients with a diagnosis of COXPD14 or those with suspected mitochondrial disorders who present with infantile seizures. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in FARS2.

Gene

Official Gene Symbol OMIM ID
FARS2 611592
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Combined oxidative phosphorylation deficiency 14 AR 614946

Related Test

Name
Leigh and Leigh-Like Syndrome Panel (Nuclear Genes Only)

Citations

  • Almalki A, Alston CL, Parker A, Simonic I, Mehta SG, He L, Reza M, Oliveira JMA, Lightowlers RN, McFarland R, Taylor RW, Chrzanowska-Lightowlers ZMA. 2014. Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency. Biochim Biophys Acta 1842: 5664. PubMed ID: 24161539
  • Elo JM, Yadavalli SS, Euro L, Isohanni P, Gotz A, Carroll CJ, Valanne L, Alkuraya FS, Uusimaa J, Paetau A, Caruso EM, Pihko H, et al. 2012. Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Human Molecular Genetics 21: 45214529. PubMed ID: 22833457
  • Shamseldin HE, Alshammari M, Al-Sheddi T, Salih MA, Alkhalidi H, Kentab A, Repetto GM, Hashem M, Alkuraya FS. 2012. Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. Journal of Medical Genetics 49: 234241. PubMed ID: 22499341

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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