Submission Details

The relationship between HYAL1 and Mucopolysaccharidosis IX (MPS IX), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of November, 2022. HYAL1 encodes a lysosomal enzyme, hyaluronidase 1, which breaks down hyaluronic acid or hyaluronan (HA), one of the major glycosaminoglycans of the extracellular matrix, especially of soft connective tissue. MPS IX or hyaluronidase deficiency is characterized by short stature, dysmoprhic features, periarticular masses, generalized swelling and elevated serum HA. MPS IX may also present similar to juvenile idiopathic arthritis. HYAL1 was first reported in relation to autosomal recessive MPS IX in 1999 (Triggs-Raine et al, PMID: 10339581). Variants reported in this gene are mostly putative loss of function variants, all of them being nonsense and frameshift variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (4.6 points): There have only been 2 published patients (and two siblings of one of the probands, PMID: 21559944) from 3 publications, till date, reported with biallelic variants in HYAL1 (PMID: 8793927, 10339581, 21559944). The mechanism of disease is loss of function.

Summary of experimental data (2.5 points): This gene-disease association is supported by expression assays and an animal model. HYAL1 is highly expressed in the liver, which is the site of hyaluronidase degradation. It is absent in the brain, which correlates with the absence of neurological features in patients with MPS IX (PMID: 10339581). The HYAL1 knock-out mouse model shows absence of hyaluronidase activity, pericellular accumulation of HA and bony outgrowth development, consistent with osteoarthritis (PMID: 18344557) and reduced bone mineral density (PMID: 35710820).

In summary, the level of evidence to support the gene-disease relationship of HYAL1 an autosomal recessive MPS IX is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was first approved by the ClinGen Lysosomal Diseases GCEP on Dec 6 2022 and was re-evaluted, with no changes, on Sept 12, 2025 (SOP v11).

The relationship between HYAL1 and Mucopolysaccharidosis IX (MPS IX), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of November, 2022. HYAL1 encodes a lysosomal enzyme, hyaluronidase 1, which breaks down hyaluronic acid or hyaluronan (HA), one of the major glycosaminoglycans of the extracellular matrix, especially of soft connective tissue. MPS IX or hyaluronidase deficiency is characterized by short stature, dysmoprhic features, periarticular masses, generalized swelling and elevated serum HA. MPS IX may also present similar to juvenile idiopathic arthritis. HYAL1 was first reported in relation to autosomal recessive MPS IX in 1999 (Triggs-Raine et al, PMID: 10339581). Variants reported in this gene are mostly putative loss of function variants, all of them being nonsense and frameshift variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (4.6 points): There have only been 2 published patients (and two siblings of one of the probands, PMID: 21559944) from 3 publications, till date, reported with biallelic variants in HYAL1 (PMID: 8793927, 10339581, 21559944). The mechanism of disease is loss of function.

Summary of experimental data (2.5 points): This gene-disease association is supported by expression assays and an animal model. HYAL1 is highly expressed in the liver, which is the site of hyaluronidase degradation. It is absent in the brain, which correlates with the absence of neurological features in patients with MPS IX (PMID: 10339581). The HYAL1 knock-out mouse model shows absence of hyaluronidase activity, pericellular accumulation of HA and bony outgrowth development, consistent with osteoarthritis (PMID: 18344557) and reduced bone mineral density (PMID: 35710820).

In summary, the level of evidence to support the gene-disease relationship of HYAL1 an autosomal recessive MPS IX is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was first approved by the ClinGen Lysosomal Diseases GCEP on Dec 6 2022 and was re-evaluted, with no changes, on Sept 12, 2025.