Gene Validity Curation

IDUA - mucopolysaccharidosis type 1

Gene: IDUA (HGNC:5391)
Classification - 05/27/2020
Disease: mucopolysaccharidosis type 1 (MONDO_0001586)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: General Gene Curation EP
Evidence Summary: The relationship between IDUA and mucopolysaccharidosis type 1 (MPS 1), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 30, 2020. IDUA encodes alpha-L-iduronidase, a lysosomal hydrolase involved in the degradation of the sulfated glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate. Deficiency of alpha-L-iduronidase results in the lysosomal accumulation of dermatan sulfate and heparan sulfate. The resulting clinical phenotype, MPS 1, is a progressive multisystem disease. Historically, patients have been categorized as either Hurler (early onset, most severe), Scheie (later onset, least severe), or Hurler-Scheie (intermediate) phenotypes. However, the MPS 1 has a clinically continuous spectrum from severe to mild and, more recently, patients have been described as either “severe” or “attenuated” MPS 1 (see GeneReviews, Clarke, 2016, https://www.ncbi.nlm.nih.gov/books/NBK1162/). Children with severe MPS1 may have nonspecific symptoms, such as umbilical or inguinal hernia, or frequent upper respiratory-tract infections in the first year of life. These children develop coarse of the facial features, gibbus deformity of the lower spine, progressive skeletal dysplasia (dysostosis multiplex), and decreased linear growth, as well as progressive and profound intellectual disability, and hearing loss. Death, usually caused by cardiorespiratory failure, typically occurs by age 10 years. The severity and rate of disease progression ranges in individuals with attenuated MPS1 from serious life-threatening complications leading to death in the second to third decades to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. Learning difficulties are present in some individuals (from GeneReviews, Clarke, 2016, https://www.ncbi.nlm.nih.gov/books/NBK1162/). Variants in IDUA were first reported in humans with MPS 1 in 1992 (Scott et al, PMID 1301196). Since then, over 200 variants in IDUA have been reported (PMID 29393969). The most commonly reported variants are p.Gln70Ter and p.Trp402Ter (PMID 29393969). The mechanism of disease is loss of function. Evidence supporting this gene-disease relationship includes case-level and experimental data. Thirteen variants in twelve probands from six publications were curated (Scott et al, 1992, PMID 1301196; Yamagishi et al, 1996, PMID 8664897; Vazna et al, 2009, PMID 19396826; Chkioua et al, 2011, PMID 22074387; Bertola et al, 2011, PMID 21394825; Ngiwsara et al, 2018, PMID 29282708) and included frameshift, nonsense, splice site, missense, and stop loss variants. More information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the function of alpha-L-iduronidase, which is consistent with the accumulation of GAGs observed in patients (Dorfman et al, 1976, PMID 813230), functional studies in fibroblasts from patients with MPS 1 (Ashton et al, 1992, PMID 1550122), the biochemical and clinical features of a mouse model with a variant analogous to a human IDUA variant causing MPS1 (Wang et al, 2010, PMID 19751987), and the impact of enzyme replacement therapy with recombinant alpha-L-iduronidase, on clinical phenotype (Clarke et al, 2009, PMID 19117887). More information is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, IDUA is definitively associated with MPS 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity assessment includes data curated by Myriad Women’s Health.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 10
17.5
12
Vazna A et al. 2009 May (PMID:19396826); Yamagishi A et al. 1996 (PMID:8664897); Chkioua L et al. 2011 Nov 10 (PMID:22074387); Ngiwsara L et al. 2018 May (PMID:29282708); Bertola F et al. 2011 Jun (PMID:21394825); Scott HS et al. 1992 (PMID:1301196);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
3
Vazna A et al. 2009 May (PMID:19396826); Yamagishi A et al. 1996 (PMID:8664897); Ngiwsara L et al. 2018 May (PMID:29282708);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
2
2
Dorfman A et al. 1976 Feb (PMID:813230);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Ashton LJ et al. 1992 Apr (PMID:1550122);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 4 4
Wang D et al. 2010 Jan (PMID:19751987);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4 1
4
Clarke LA et al. 2009 Jan (PMID:19117887);
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/27/2020
EXPERT CURATION (DATE)
Definitive
05/27/2020
EVIDENCE SUMMARY
The relationship between IDUA and mucopolysaccharidosis type 1 (MPS 1), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 30, 2020. IDUA encodes alpha-L-iduronidase, a lysosomal hydrolase involved in the degradation of the sulfated glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate. Deficiency of alpha-L-iduronidase results in the lysosomal accumulation of dermatan sulfate and heparan sulfate. The resulting clinical phenotype, MPS 1, is a progressive multisystem disease. Historically, patients have been categorized as either Hurler (early onset, most severe), Scheie (later onset, least severe), or Hurler-Scheie (intermediate) phenotypes. However, the MPS 1 has a clinically continuous spectrum from severe to mild and, more recently, patients have been described as either “severe” or “attenuated” MPS 1 (see GeneReviews, Clarke, 2016, https://www.ncbi.nlm.nih.gov/books/NBK1162/). Children with severe MPS1 may have nonspecific symptoms, such as umbilical or inguinal hernia, or frequent upper respiratory-tract infections in the first year of life. These children develop coarse of the facial features, gibbus deformity of the lower spine, progressive skeletal dysplasia (dysostosis multiplex), and decreased linear growth, as well as progressive and profound intellectual disability, and hearing loss. Death, usually caused by cardiorespiratory failure, typically occurs by age 10 years. The severity and rate of disease progression ranges in individuals with attenuated MPS1 from serious life-threatening complications leading to death in the second to third decades to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. Learning difficulties are present in some individuals (from GeneReviews, Clarke, 2016, https://www.ncbi.nlm.nih.gov/books/NBK1162/). Variants in IDUA were first reported in humans with MPS 1 in 1992 (Scott et al, PMID 1301196). Since then, over 200 variants in IDUA have been reported (PMID 29393969). The most commonly reported variants are p.Gln70Ter and p.Trp402Ter (PMID 29393969). The mechanism of disease is loss of function. Evidence supporting this gene-disease relationship includes case-level and experimental data. Thirteen variants in twelve probands from six publications were curated (Scott et al, 1992, PMID 1301196; Yamagishi et al, 1996, PMID 8664897; Vazna et al, 2009, PMID 19396826; Chkioua et al, 2011, PMID 22074387; Bertola et al, 2011, PMID 21394825; Ngiwsara et al, 2018, PMID 29282708) and included frameshift, nonsense, splice site, missense, and stop loss variants. More information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the function of alpha-L-iduronidase, which is consistent with the accumulation of GAGs observed in patients (Dorfman et al, 1976, PMID 813230), functional studies in fibroblasts from patients with MPS 1 (Ashton et al, 1992, PMID 1550122), the biochemical and clinical features of a mouse model with a variant analogous to a human IDUA variant causing MPS1 (Wang et al, 2010, PMID 19751987), and the impact of enzyme replacement therapy with recombinant alpha-L-iduronidase, on clinical phenotype (Clarke et al, 2009, PMID 19117887). More information is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, IDUA is definitively associated with MPS 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity assessment includes data curated by Myriad Women’s Health.