TY - JOUR
T1 - Structure and Function of the ABCD1 Variant Database
T2 - 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy
AU - Mallack, Eric J.
AU - Gao, Kerry
AU - Engelen, Marc
AU - Kemp, Stephan
N1 - Funding Information: Funding: This research was funded by the National Institutes of Health, grant number K23NS118044 to EM; the Netherlands Organization for Scientific Research, grant number 016.196.310 to ME; and the Netherlands Organization for Health Research and Development, grant number 543002004 to SK. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonran-dom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.
AB - The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonran-dom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.
KW - ABC transporter
KW - ABCD1
KW - Adrenoleukodystrophy
KW - Diagnosis
KW - Genetics
KW - Mutation
KW - Newborn screening
KW - Peroxisome
KW - Variants of uncertain significance
UR - http://www.scopus.com/inward/record.url?scp=85122896910&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells11020283
DO - https://doi.org/10.3390/cells11020283
M3 - Article
C2 - 35053399
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 2
M1 - 283
ER -