Submission Details

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.