Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.
Genotype–phenotype relationship
Mass spectrometry
Metachromatic leukodystrophy
Mutation
Newborn screening
Phenotype
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
21 07 2023
21 07 2023
Historique:
received:
26
07
2022
accepted:
29
06
2023
medline:
24
7
2023
pubmed:
22
7
2023
entrez:
21
7
2023
Statut:
epublish
Résumé
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene (ARSA) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutants remains unknown; better understanding of the genotype-phenotype relationship is required to support newborn screening (NBS) and guide treatment. We collected a patient data set from the literature that relates disease severity to ARSA genotype in 489 individuals with MLD. Patient-based data were used to develop a phenotype matrix that predicts MLD phenotype given ARSA alleles in a patient's genotype with 76% accuracy. We then employed a high-throughput enzyme activity assay using mass spectrometry to explore the function of ARSA variants from the curated patient data set and the Genome Aggregation Database (gnomAD). We observed evidence that 36% of variants of unknown significance (VUS) in ARSA may be pathogenic. By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes of unknown significance (GUS) by over 98.5% in the overall population. These results provide an additional tool for clinicians to anticipate the disease course in MLD patients, identifying individuals at high risk of severe disease to support treatment access. Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic. We show that combining genetic and biochemical information increases diagnostic yield. Our strategy may apply to other recessive diseases, providing a tool to address the challenge of interpreting VUS within genotype-phenotype relationships and NBS.
Sections du résumé
BACKGROUND
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene (ARSA) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutants remains unknown; better understanding of the genotype-phenotype relationship is required to support newborn screening (NBS) and guide treatment.
RESULTS
We collected a patient data set from the literature that relates disease severity to ARSA genotype in 489 individuals with MLD. Patient-based data were used to develop a phenotype matrix that predicts MLD phenotype given ARSA alleles in a patient's genotype with 76% accuracy. We then employed a high-throughput enzyme activity assay using mass spectrometry to explore the function of ARSA variants from the curated patient data set and the Genome Aggregation Database (gnomAD). We observed evidence that 36% of variants of unknown significance (VUS) in ARSA may be pathogenic. By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes of unknown significance (GUS) by over 98.5% in the overall population.
CONCLUSIONS
These results provide an additional tool for clinicians to anticipate the disease course in MLD patients, identifying individuals at high risk of severe disease to support treatment access. Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic. We show that combining genetic and biochemical information increases diagnostic yield. Our strategy may apply to other recessive diseases, providing a tool to address the challenge of interpreting VUS within genotype-phenotype relationships and NBS.
Identifiants
pubmed: 37480112
doi: 10.1186/s13059-023-03001-z
pii: 10.1186/s13059-023-03001-z
pmc: PMC10360315
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
172Subventions
Organisme : NIH HHS
ID : R01 DK067859
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Neurology. 2019 Oct 29;93(18):e1742-e1743
pubmed: 31659141
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Clin Genet. 2008 Oct;74(4):349-57
pubmed: 18786133
Proc Natl Acad Sci U S A. 1989 Dec;86(23):9436-40
pubmed: 2574462
Arq Neuropsiquiatr. 2016 Dec;74(12):953-966
pubmed: 27991992
J Hum Genet. 2019 Apr;64(4):323-331
pubmed: 30674982
Nat Methods. 2015 Nov;12(11):1002-3
pubmed: 26513549
J Neurol Sci. 2011 Feb 15;301(1-2):38-45
pubmed: 21167507
Exp Ther Med. 2019 Sep;18(3):1738-1744
pubmed: 31410132
Hum Mutat. 2016 Jan;37(1):16-27
pubmed: 26462614
Gene. 2013 Nov 10;530(2):323-8
pubmed: 24001781
Hum Mutat. 2017 Nov;38(11):1511-1520
pubmed: 28762252
Mol Genet Metab. 2003 Jun;79(2):83-90
pubmed: 12809637
Hum Mutat. 1994;4(2):119-27
pubmed: 7981715
Hum Mutat. 2007 Sep;28(9):897-903
pubmed: 17458871
Nat Genet. 2014 Sep;46(9):944-50
pubmed: 25086666
Hum Mutat. 2018 Dec;39(12):1854-1860
pubmed: 30260545
Hum Mutat. 1998;Suppl 1:S254-6
pubmed: 9452102
J Mol Neurosci. 2021 Feb;71(2):245-251
pubmed: 32617873
Orphanet J Rare Dis. 2015 Nov 09;10:144
pubmed: 26553228
Genet Med. 2021 Mar;23(3):555-561
pubmed: 33214709
Orphanet J Rare Dis. 2012 Jun 07;7:35
pubmed: 22676651
Clin Chim Acta. 2016 Sep 1;460:135-7
pubmed: 27374302
Dement Geriatr Cogn Disord. 2001 Mar-Apr;12(2):85-8
pubmed: 11173879
Clin Genet. 2009 Jan;75(1):57-64
pubmed: 19021637
J Neurosci Res. 2016 Nov;94(11):1076-83
pubmed: 27638593
Neurol Res. 2009 Feb;31(1):60-6
pubmed: 18768108
Hum Mutat. 1999;14(3):240-8
pubmed: 10477432
BMC Med Genomics. 2018 Mar 27;11(1):35
pubmed: 29580235
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Anal Chem. 2020 May 5;92(9):6341-6348
pubmed: 31922725
Neuroradiol J. 2016 Apr;29(2):134-6
pubmed: 26915897
Pediatr Neurol. 2007 Jun;36(6):397-401
pubmed: 17560502
Hum Mutat. 2019 Sep;40(9):1519-1529
pubmed: 31342580
PLoS One. 2018 Jul 6;13(7):e0200008
pubmed: 29979746
J Biol Chem. 2002 Mar 15;277(11):9455-61
pubmed: 11777924
N Engl J Med. 1991 Jan 3;324(1):18-22
pubmed: 1670590
Am J Hum Genet. 1991 Dec;49(6):1340-50
pubmed: 1684088
Hum Mol Genet. 1998 Aug;7(8):1215-9
pubmed: 9668161
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020 Feb 10;37(2):153-155
pubmed: 32034743
Hum Mutat. 1997;9(3):234-42
pubmed: 9090526
Int J Genomics. 2018 Jul 03;2018:2361068
pubmed: 30057904
Genet Med. 2005 Feb;7(2):119-23
pubmed: 15714079
Genet Mol Biol. 2017 Oct-Dec;40(4):759-762
pubmed: 29111560
JIMD Rep. 2012;6:117-25
pubmed: 23430949
Am J Hum Genet. 1993 Aug;53(2):339-46
pubmed: 8101038
BMC Res Notes. 2019 Nov 6;12(1):726
pubmed: 31694723
Mol Genet Metab Rep. 2019 Feb 20;19:100460
pubmed: 30828547
PLoS One. 2018 Jun 18;13(6):e0199048
pubmed: 29912909
Science. 2013 Aug 23;341(6148):1233158
pubmed: 23845948
Hum Genet. 2002 Apr;110(4):351-5
pubmed: 11941485
Acta Endocrinol (Buchar). 2018 Jan-Mar;14(1):131
pubmed: 31149247
Ann Neurol. 1992 Mar;31(3):256-61
pubmed: 1353340
ScientificWorldJournal. 2019 Mar 20;2019:5198931
pubmed: 31015822
J Alzheimers Dis. 2016;51(3):683-7
pubmed: 26890752
J Mol Neurosci. 2017 Sep;63(1):84-90
pubmed: 28799099
J Mol Neurosci. 2018 Sep;66(1):17-25
pubmed: 30083785
Neuromuscul Disord. 2015 Sep;25(9):719-24
pubmed: 26231297
Best Pract Res Clin Endocrinol Metab. 2015 Mar;29(2):261-73
pubmed: 25987178
Sci Rep. 2017 May 31;7(1):2543
pubmed: 28566687
Orphanet J Rare Dis. 2019 Jun 11;14(1):136
pubmed: 31186049
Hum Mutat. 2003 Nov;22(5):418-9
pubmed: 14517960
Am J Hum Genet. 2016 Oct 6;99(4):877-885
pubmed: 27666373
J Clin Neurosci. 2006 May;13(4):443-8
pubmed: 16678723
J Clin Epidemiol. 2003 Nov;56(11):1129-35
pubmed: 14615004
J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):655-7
pubmed: 15026521
Am J Med Genet A. 2004 Sep 1;129A(3):277-81
pubmed: 15326627
Hum Genet. 1991 Mar;86(5):463-70
pubmed: 1673113
Arch Argent Pediatr. 2019 Feb 1;117(1):e52-e55
pubmed: 30652456
Orphanet J Rare Dis. 2016 May 18;11(1):65
pubmed: 27189384
Mol Genet Metab. 2003 Nov;80(3):360-3
pubmed: 14680985
Nat Genet. 2014 Mar;46(3):299-304
pubmed: 24509478
Ther Clin Risk Manag. 2017 Jun 16;13:725-731
pubmed: 28670130
J Inherit Metab Dis. 2017 Jul;40(4):543-554
pubmed: 28560469
J Child Neurol. 2016 Mar;31(3):338-44
pubmed: 26187619
J Mol Neurosci. 2013 Jun;50(2):284-90
pubmed: 23559313
Neurology. 2016 Jul 5;87(1):103-11
pubmed: 27261095
Hum Mutat. 2008 Nov;29(11):E220-30
pubmed: 18693274
JAMA Neurol. 2013 Jun;70(6):779-82
pubmed: 23608771
Lancet. 2016 Jul 30;388(10043):476-87
pubmed: 27289174
Mol Genet Metab. 2011 Jul;103(3):300-2
pubmed: 21514195
J Neurol. 2014 Jan;261(1):83-97
pubmed: 24158270