الملخص الإنجليزي
Mucopolysaccharidoses (MPS) type III known as Sanfilippo syndrome, which is a
multisystem lysosomal storage disorder that is characterized by central nervous system
degeneration and extreme clinical variability. There are four types of MPS III (A, B, C,
and D). All of them are autosomal recessive diseases. Each type is associated with a
specific enzyme deficiency that catabolizes the heparan sulfate macromolecule and
presents with a wider range of symptoms, including both mental and physical. To the
best of our knowledge, there have been no molecular studies conducted on MPS III
disease in Oman, and the genetic mutation causing MPS III subtypes remains to be
elucidated. Moreover, there is limited knowledge about founder mutations, genotypephenotype correlations, and the functional effect of these mutations on corresponding
proteins. Therefore, this project aimed at identifying MPS III causal mutations in Omani
patients, functional characterization of causal mutations, understand the phenotypegenotype correlation, and establish a local targeted panel for MPS III patients. Thirteen
patients with MPS III, diagnosed from January 2011 to December 2021 at the Royal
Hospital, were enrolled. The whole exome sequencing (WES) approach was used to
identify causal mutations. Identified variants were validated using sanger sequencing,
and characterized using bioinformatics tools and databases. We identified and
characterized six mutations in Omani patients with Sanfilippo syndrome. Three of them
were novel. In the SGSH gene, two mutations, c.1175delT (p.Phe392Serfs*21) and
c.48C>T, were associated with MPS IIIA. In cases with MPS IIIB, three mutations were
identified in the NAGLU gene (c.239C>T (p. Ser80Phe), c.746T>A (p.Val249Asp), and
c.1669_1670insAGCAGGTCCA, (p.Arg557Glnfs*24). In the MPS IIIC patient, a novel
mutation (c.835G>A, p. Asp279Asn) was identified in exon 9 of the HGSNAT gene.
Notably, all associated variants were homozygous, which suggested mutation
inheritance from a common ancestor. In fact, patients sharing the same variant belong to
the same family, tribe, or region. The identified variants are associated with a wide
spectrum of clinical phenotypes that may to an extend explain disease heterogeneity.
Furthermore, a local diagnostic and prognostic panel for MPS III was established.
Finally, we hope the data generated from this project will be used for understanding
disease heterogeneity, and selecting an appropriate therapeutic approach.
