Elevated Levels of C0/(C16+C18) Acylcarnitine via the CPT1A Gene

Newborn screening (NBS) tests are performed soon after birth with the goal of identifying individuals that may be affected by certain disorders before disease-related disability or death occurs. Appropriate medical management beginning early in life can prevent all or many symptoms in the affected individuals (Watson et al. 2006. PubMed ID: 16783161; https://www.cdc.gov/newbornscreening/). While NBS is required within all states and territories in the United States, individual state or territory public health departments determine which conditions are included on the NBS panel (https://www.babysfirsttest.org/newborn-screening/states). NBS protocols outside of the United States vary from country to country. At a minimum, all core conditions on the Recommended Uniform Screening Panel (RUSP) should be included on NBS panels within the United States. In addition, NBS testing may also include secondary conditions, which are disorders that can be detected as part of the differential diagnosis of a core condition (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). Following an abnormal NBS result, follow up diagnostic testing is indicated. Such testing may include biochemical methodologies (for example, urine organic acid analysis or plasma acylcarnitine analysis), enzyme assays, and/or molecular genetic testing.

This test is designed for individuals with NBS results showing elevated levels of C0/(C16+C18) acylcarnitine ratio which can indicate carnitine palmitoyltransferase 1A deficiency. CPT1A deficiency is a core condition on the RUSP.

Carnitine palmitoyltransferase 1A deficiency is an autosomal recessive rare disorder, and CPT1A is the only gene that is known to be involved. The majority of pathogenic variants are missense, though one small in-frame deletion as well as nonsense and other premature termination variants (small insertions, deletions, and splice variants) have also been reported. Two gross deletions have been reported (Human Gene Mutation Database). At least three variants have been reported at higher frequencies in specific populations. The p.G710E variant is common among North American Hutterites, the p.P479L variant is common among Alaskan Native populations and other Inuit and artic populations, and the p.K455T variant is common among Finnish patients (Prasad et al. 2001. PubMed ID: 11350183;Greenberg et al. 2009. PubMed ID: 19217814; Gillingham et al. 2011. PubMed ID: 21763168; Clemente et al. 2014. PubMed ID: 25449608; Roomets et al. 2012. PubMed ID: 21962599).

The carnitine palmitoyltransferase system is comprised of several proteins with enzyme and transporter functions. These proteins are involved in long-chain fatty acid (LCFA) metabolism, being specifically responsible for the net transport of LCFAs from the cytosol into the mitochondrial matrix. The CPT1 protein is the first component of this system. CPT1 activates LCFAs by catalyzing the transfer of an acyl group to carnitine, which is then transported into the mitochondrial matrix. Multiple isoforms of CPT1 exist. The CPT1A isoform is expressed predominantly in the liver and is the only isoform that has thus far been associated with human disease (Brown et al. 2001. PubMed ID: 11441142; Bonnefont et al. 2004. PubMed ID: 15363638).

Clinical sensitivity of this test is expected to be high for patients with confirmed carnitine palmitoyltransferase 1A deficiency as, to date, nearly all reported patients have had two pathogenic variants detectable via sequencing. Based on combined results from several studies, 55 pathogenic alleles were identified in 29 affected patients for an overall sensitivity of ~95% (Brown et al. 2001. PubMed ID: 11441142; Gobin et al. 2002. PubMed ID: 12189492; Bennett et al. 2004. PubMed ID: 15110323; Greenberg et al. 2009. PubMed ID: 19217814; Fontaine et al. 2012. PubMed ID: 23430932; Roomets et al. 2012. PubMed ID: 21962599).

Only two gross deletions have been reported in the CPT1A gene (Gobin et al. 2002. PubMed ID: 12189492; Zhang et. al. 2021. PubMed ID: 34869124). Therefore, the sensitivity of duplication/deletion testing for this rare disorder, although not precisely known, is expected to be low.

This test provides full coverage of all coding exons of the CPT1A 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).