Elevated C5-DC Acylcarnitine via the GCDH 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 C5-DC acylcarnitine, which can indicate a deficiency of the glutaryl-CoA dehydrogenase (GCDH) enzyme. GCDH deficiency is a core condition on the RUSP. 

Individuals with GCDH deficiency may be unaffected during the newborn period but are at risk of acute encephalopathic crises triggered by common illnesses (Hoffmann et al. 1995. PubMed ID: 7564239; https://www.acmg.net/PDFLibrary/C5-DC.pdf). The overall prevalence of GCDH deficiency is estimated at ~1/100,000 worldwide, though it can be significantly higher in certain populations (Kölker et al. 2007. PubMed ID: 17622945; Larson and Goodman 2019. PubMed ID: 31536184). 

Glutaryl-CoA dehydrogenase (GCDH) deficiency, also known as glutaric acidemia type I, is an autosomal recessive disorder. Over 350 pathogenic variants have been reported in the GCDH gene in the HGMD and ClinVar databases (https://www.hgmd.cf.ac.uk/; https://www.ncbi.nlm.nih.gov/clinvar/), with the majority being missense changes. Relatively fewer nonsense, splice site, and small insertion/deletion variants are reported, and copy number variants (CNVs) have only rarely been reported (Larson and Goodman 2019. PubMed ID: 31536184). Variants are found in every GCDH exon (Goodman et al. 1998. PubMed ID: 9711871). Several founder variants have been reported in a variety of populations: the Ojibway-Cree First Nations Canadians (c.91+5G>T), the South African Xhosa population (c.877G>A, p.Ala293Thr), the Irish Traveler communities in the Republic of Ireland (c.1093G>A, p.Glu365Lys), the Lumbee Native Americans of North Carolina (c.1240G>A, p.Glu414Lys), and the Pennsylvania Amish (c.1262C>T, p.Ala411Val) (Larson and Goodman 2019. PubMed ID: 31536184). Several other variants are also common in individuals from a variety of populations: c.680G>C, p.Arg227Pro; c.1198G>A, p.Val400Met; c.1213A>G, p.Met405Val; c.541G>C, p.Glu181Gln; c.1204C>T, p.Arg402Trp (Larson and Goodman 2019. PubMed ID: 31536184). The most common pan-ethnic variant, c.1204C>T, p.Arg402Trp, is reported in the gnomAD database with a maximum minor allele frequency of 0.076% (https://gnomad.broadinstitute.org/). To our knowledge, de novo variants in GCDH have not been reported. 

Pathogenic variants in the GCDH gene lead to disruption of the glutaryl-CoA dehydrogenase enzyme, which is an enzyme in the lysine degradation pathway. Deficiency of this enzyme results in elevation of glutaric acid, glutarylcarnitine (C5-DC), and other toxic metabolites (https://www.acmg.net/PDFLibrary/C5-DC.pdf; http://www.iembase.com/disorder/163).

Based on studies of individuals with a diagnosis of glutaric acidemia type I, approximately 95-100% of expected GCDH variants are identified by molecular testing (Schwartz et al. 1998. PubMed ID: 9600243; Zschocke et al. 2000. PubMed ID: 10699052; Mosaeilhy et al. 2017. PubMed ID: 28389991; Larson and Goodman 2019. PubMed ID: 31536184; Kilavuz et al. 2021. PubMed ID: 33578440). 

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