Dataset Information

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.

SUBMITTER: Miller MJ

PROVIDER: S-EPMC4790081 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Miller Marcus J MJ Burrage Lindsay C LC Gibson James B JB Strenk Meghan E ME Lose Edward J EJ Bick David P DP Elsea Sarah H SH Sutton V Reid VR Sun Qin Q Graham Brett H BH Craigen William J WJ Zhang Victor Wei VW Wong Lee-Jun C LJ

Molecular genetics and metabolism 20150902 3

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 ACAD ...[more]

PMID: 26385305

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Project description:Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of fatty acid metabolism with a variable presentation. The aim of this study was to describe five patients with VLCADD diagnosed through the pilot study and expanded newborn screening (NBS) program that started in 2018 in Slovenia. Four patients were diagnosed through the expanded NBS program with tandem mass spectrometry; one patient was previously diagnosed in a pilot study preceding the NBS implementation. Confirmatory testing consisted of acylcarnitines analysis in dried blood spots, organic acids profiling in urine, genetic analysis of ACADVL gene, and enzyme activity determination in lymphocytes or fibroblasts. Four newborns with specific elevation of acylcarnitines diagnostic for VLCADD and disease-specific acylcarnitines ratios (C14:1, C14, C14:2, C14:1/C2, C14:1/C16) were confirmed with genetic testing: all were compound heterozygotes, two of them had one previously unreported ACDVL gene variant each (NM_000018.3) c.1538C > G; (NP_000009) p.(Ala513Gly) and c.661A > G; p.(Ser221Gly), respectively. In addition, one patient diagnosed in the pilot study also had a specific elevation of acylcarnitines. Subsequent ACDVL genetic analysis confirmed compound heterozygosity. In agreement with the diagnosis, enzyme activity was reduced in five patients tested. In seven other newborns with positive screening results, only single allele variants were found in the ACDVL gene, so the diagnosis was not confirmed. Among these, two variants were novel, c.416T > C and c.1046C > A, respectively (p.Leu139Pro and p.Ala349Glu). In the first 2 years of the expanded NBS program in Slovenia altogether 30,000 newborns were screened. We diagnosed four cases of VLCADD. The estimated VLCADD incidence was 1:7,500 which was much higher than that of the medium-chain acyl-CoA dehydrogenase deficiency (MCADD) cases in the same period. Our study also provided one of the first descriptions of ACADVL variants in Central-Southeastern Europe and reported on 4 novel variants.

Project description:BackgroundVery-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is diagnosed in the US through newborn screening (NBS). NBS often unequivocally identifies affected individuals, but a growing number of variant patterns can represent mild disease or heterozygous carriers.AimsTo evaluate the validity of standard diagnostic procedures for VLCADD by using functional in vitro tools.MethodsWe retrospectively investigated 13 patient samples referred to our laboratory because of a suspicion of VLCADD but with some uncertainty to the diagnosis. All 13 patients were suspected of having VLCADD either because of abnormal NBS or suggestive clinical findings. ACADVL genomic DNA sequencing data were available for twelve of them. Ten of the patients had an abnormal NBS suggestive of VLCADD, with three samples showing equivocal results. Three exhibited suggestive clinical findings and blood acylcarnitine profile (two of them had a normal NBS and the third one was unscreened). Assay of VLCAD activity and immunoblotting or immunohistologic staining for VLCAD were performed on fibroblasts. Prokaryotic mutagenesis and expression studies were performed for nine uncharacterized ACADVL missense mutations.ResultsVLCAD activity was abnormal in fibroblast cells from 9 patients (8 identified through abnormal NBS, 1 through clinical symptoms). For these 9 patients, immunoblotting/staining showed the variable presence of VLCAD; all but one had two mutated alleles. Two patients with equivocal NBS results (and a heterozygous genotype) and the two patients with normal NBS exhibited normal VLCAD activity and normal VLCAD protein on immunoblotting/staining thus ruling out VLCAD deficiency. Nine pathogenic missense mutations were characterized with prokaryotic expression studies and showed a decrease in enzyme activity and variable stability of VLCAD antigen.ConclusionsThese results emphasize the importance of functional investigation of abnormal NBS or clinical testing suggestive but not diagnostic of VLCADD. A larger prospective study is necessary to better define the clinical and metabolic ramifications of the defects identified in such patients.

Dataset Information

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Publications

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

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