Mucopolysaccharidosis Type IX via the HYAL1 Gene

The mucopolysaccharidoses (MPS) are a group of inherited disorders caused by defects in lysosomal enzymes responsible for degradation of glycosaminoglycans (GAGs). Each enzyme deficiency results in progressive storage of distinct GAGs in multiple organ systems and subsequent abnormalities. Although MPS share several symptoms, including physical and mental developmental abnormalities, they may differ even within the same enzyme deficiency. MPS are classified in seven groups on the basis of the clinical symptoms (Types I, II, III, IV, VI, VII, and IX). Defects in eleven different enzymes have been connected with the various MPS (Neufeld and Muenzer 2001).

MPS IX is caused by hyaluronidase deficiency and subsequent accumulation of lysosomal hyaluronan. Only two instances of the condition have been reported. The first case is the only affected daughter of a non-consanguineous family. She presented, at the age of 7.5 years, with a soft tissue mass over an ankle. Additional features appeared later and include recurrent infections and periarticular soft-tissue masses accompanied by episodes of painful swelling that resolved within a 3-day period. These episodes started toward the end of the first decade of life. Stature of this patient was short; while visceral and mental development were normal (Natowicz et al. 1996). More recently, MPS IX was described in three affected children from a consanguineous family. In this family, the clinical features are restricted to painful swelling of the knees and/or hips. MRI findings indicated inflammation of the synovial membrane of joints (synovitis) (Imundo et al. 2011).

MPS IX is an exceptionally rare disorder, with an estimated prevalence of less than 1 in 1,000,000 live births (Orphanet).

MPS IX is inherited in an autosomal recessive manner. It is caused by defects in the HYAL1 gene. Only three pathogenic variants in HYAL1 have been reported to date. Two of these were identified in the patient reported by Natowicz et al. (1996). The first is a missense variant defined as c.1412G>A (p.Glu268Lys). The second consists of a complex rearrangement defined as c.1361del37ins14 and predicted to result in premature protein termination (Triggs-Raine et al. 1999). A homozygous single nucleotide deletion (c.104delT) that is predicted to result in a truncated protein was identified in the affected members of the recently reported consanguineous family (Imundo et al. 2011).

The HYAL1 gene encodes the hyaluronidase enzyme, which catalyzes the degradation of hyaluronan, one of the main glycosaminoglycans of the extracellular matrix.

Unknown, but HYAL1 mutations appear to be a rare cause of MPS (ORPHANET).

So far, no gross deletions or duplications have been reported in HYAL1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the HYAL1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).