Identification of genetic variants in 79 Argentinean patients with mucopolysaccharidosis type II (Hunter syndrome)

RICCHERI C; AMARTINO H; CECI R; ROZENFELD, PAULA ADRIANA

Simposio; Lysosomal Disease Network-17th Annual WORLD Symposium; 2023

Hunter disease is a rare X-linked lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS) due to pathogenic variants in IDS gene located on chromosome Xq28. MPS II is a multisystemic, chronic and progressive disorder with a variability in the rate of signs and symptoms among patients with a spectrum of phenotypes, ranging from severe to attenuated course. To date, more than 700 variants have been communicated. We report the genotype and phenotype characterization of 79 patients from Argentina.Materials and methods Seventy-nine Hunter patients were included in this study, diagnosis was confirmed by deficient IDS activity in leukocytes, GAG urinary excretion and clinical characteristics, classified into non-neuronopathic and severe or neuronopathic forms. Genomic DNA was extracted from EDTA blood and the 9 exons of the IDS gene including exon/intron boundaries were amplified by PCR. Sequencing was carried out in both directions Recombination between IDS and IDSP1 leading to any inversion mutation was analyzed by a PCR amplification assay. Results 48 different MPS II alleles have been identified in a cohort of 79 Argentinean patients: 31 missense (65%), 5 splicing (10%), 9 short deletions (19%), 1 insertion (2%), 1 complex rearrangement (a gene–pseudogene recombination leading to inversion) (2%) and 1 gross gene deletion (2%). Of the variants, 6 out of 48 different alleles (12%) were novel: c.1030G>A, c.191T>A, c.238delC, c.326G>C, c.714delT, c.818insG. In 4 patients there was not IDS gen amplification probably due to a deletion. In 3 patients, diagnosis was performed based on family history, clinical evidence and IDS deficiency. In one patient, genomic DNA analysis by sequencing did not show any variant. ConclusionHunter syndrome is characterized by a high genetic heterogeneity, genotype-phenotype correlation is difficult to establish. In our series, c.1122C>T, c.1433A>G, c.181T>C, c.191T>A, c.253G>A, c.359C>A, c.425C>A, c.592G>A were associated with non-neuonopathic forms.