title: Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.
abstract: Very long chain acyl-coA dehydrogenase deficiency (VLCADD) is an autosomal recessive inborn error of fatty acid oxidation detected by newborn screening (NBS). Follow-up molecular analyses are often required to clarify VLCADD-suggestive NBS results, but to date the outcome of these studies are not well described for the general screen-positive population. In the following study, we report the molecular findings for 693 unrelated patients that sequentially received Sanger sequence analysis of ACADVL as a result of a positive NBS for VLCADD. Highlighting the variable molecular underpinnings of this disorder, we identified 94 different pathogenic ACADVL variants (40 novel), as well as 134 variants of unknown clinical significance (VUSs). Evidence for the pathogenicity of a subset of recurrent VUSs was provided using multiple in silico analyses. Surprisingly, the most frequent finding in our cohort was carrier status, 57% all individuals had a single pathogenic variant or VUS. This result was further supported by follow-up array and/or acylcarnitine analysis that failed to provide evidence of a second pathogenic allele. Notably, exon-targeted array analysis of 131 individuals screen positive for VLCADD failed to identify copy number changes in ACADVL thus suggesting this test has a low yield in the setting of NBS follow-up. While no genotype was common, the c.848T>C (p.V283A) pathogenic variant was clearly the most frequent; at least one copy was found in ~10% of all individuals with a positive NBS. Clinical and biochemical data for seven unrelated patients homozygous for the p.V283A allele suggests that it results in a mild phenotype that responds well to standard treatment, but hypoglycemia can occur. Collectively, our data illustrate the molecular heterogeneity of VLCADD and provide novel insight into the outcomes of NBS for this disorder.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Miller
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Burrage
authors.affiliation: Section of Clinical Genetics and Metabolism, 'Specially for Children, Austin, TX 78723, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Gibson
authors.affiliation: Children's Mercy Hospital, Kansas City, MO 64108, United States.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Strenk
authors.affiliation: Department of Genetics, University of Alabama Birmingham, Birmingham, AL 35294, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lose
authors.affiliation: Section of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Bick
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: Qin
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States.
authors.forename: Victor Wei
authors.initials: VW
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77021, United States. Electronic address: ljwong@bcm.edu.
authors.forename: Lee-Jun C
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics*; D000483:Alleles; D002331:Carnitine / Q000031:analogs & derivatives; D003198:Computer Simulation; D000080984:Congenital Bone Marrow Failure Syndromes; D005091:Exons; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D009135:Muscular Diseases / Q000175:diagnosis* / Q000235:genetics*; D020125:Mutation, Missense; D015997:Neonatal Screening; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D053719:Tandem Mass Spectrometry; D014481:United States
chemical_list: C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine
keywords: ACADVL; Fatty acid oxidation; Inborn error of metabolism; NBS; Newborn screening; V243A; V283A; VLCAD; VLCADD