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Cited by 14Metabolism and Genetic DisordersGenomics and Rare DiseasesLysosomal Storage Disorders Research

Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene

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van de Stadt, Stephanie I. W., Mooyer, Petra A. W., Dijkstra, Inge M. E., Dekker, Conny J. M., Vats, Divya, Vera, Moin, Ruzhnikov, Maura R. Z., van Haren, Keith +9 more·2021·Genes
DOI 10.3390/genes12121930PMC PMC8701351
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Abstract

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.

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  • In the case of a VUS, biochemical and functional analyses of patient fibroblasts can aid the interpretation of the variant as either a (likely) benign or pathogenic change.

    “In the case of a VUS, biochemical and functional analyses of patient fibroblasts can aid the interpretation of the variant as either a (likely) benign or pathogenic change [59].”

    From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [59]

    The Discussion reports that biochemical and functional studies of fibroblasts helped classify variants as (likely) pathogenic or benign. The study concerns VUS in the ABCD1 gene, however, so it does not establish the claim for VUS generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Authors
van de Stadt, S. I. W., Mooyer, P. A. W., Dijkstra, I. M. E., Dekker, C. J. M., Vats, D., Vera, M., Ruzhnikov, M. R. Z., van Haren, K., Tang, N., Koop, K., Willemsen, M. A., Hui, J., Vaz, F. M., Ebberink, M. S., Engelen, M., Kemp, S., & Ferdinandusse, S.
Affiliations
  • Department of Pediatric Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam Neuroscience, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
  • Amsterdam University Medical Centers (NL)
  • Kaiser Permanente (US)
  • Stanford Medicine (US)
  • Departments of Neurology and Neurological Sciences and Pediatrics, Stanford, CA 94305, USA
  • Chinese University of Hong Kong (HK)
  • University Medical Center Utrecht (NL)
  • Department of Pediatric Neurology, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands
  • Hong Kong Children's Hospital (HK)
  • Emma Kinderziekenhuis (NL)
Corresponding author
Kemp, Stephan
ORCID
Venue
Genes
Publisher
MDPI AG
Published
2021-11-30
Volume
12
Issue
12
Pages
1930
ISSN
2073-4425 (ISSN-L)
DOI
10.3390/genes12121930
PMC
PMC8701351
OpenAlex
W3216111363
Cited by
14
References
4
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 1
FWCI
1.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Genes (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (acceptedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Netherlands Organization for Scientific Research (016.196.310)
  • Netherlands Organisation for Health Research and Development (543002004)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
X-linked adrenoleukodystrophy, ABCD1 gene, variants of uncertain significance, very long chain fatty acids, peroxisomal beta-oxidation, variant pathogenicity classification, newborn screening
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Adult, Fatty Acids, Fibroblasts, Humans, Male, Middle Aged, Mutation, Reference Values

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