Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.
Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.
Smith
Emily H
EH
Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Thomas
Cheryl
C
McHugh
David
D
Gavrilov
Dimitar
D
Raymond
Kimiyo
K
Rinaldo
Piero
P
Tortorelli
Silvia
S
Matern
Dietrich
D
Highsmith
W Edward
WE
Oglesbee
Devin
D
D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D056726:Genetic Association Studies; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D005838:Genotype; D005998:Glycine / Q000031:analogs & derivatives / Q000652:urine; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology* / Q000235:genetics* / Q000652:urine; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D015997:Neonatal Screening; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
C024571:N-caproylglycine; D042964:Acyl-CoA Dehydrogenase; C008698:octanoylcarnitine; D002331:Carnitine; D005998:Glycine