Molecular characterization of a large cohort of mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis study (IMPRESsion)

Hum Mutat. 2022 Jan 10. doi: 10.1002/humu.24328.

PMID: 35005816

Saeed R Ghaffari, Maryam Rafati, Mahdi Shadnoush

Highlights: This extensive patient cohort reveals the genetic and geographic landscape of mucopolysaccharidosis (MPS) in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

Abstract

Background and objective: Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn metabolism errors (IEMs) that are detected using a combination of clinical, biochemical, and genetic tests. The goal of this work was to characterize the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families) molecularly, as well as monitor their ethnicity and geographic origins.

Methods and results: An IEM-targeted NGS panel was used to study 185/289 patients, followed by complementary Sanger sequencing, which resulted in the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). In addition, 106/289 patients who were referred with positive results underwent reanalysis and confirmatory tests, with 104 of them being diagnosed with MPS. There were 258 MPS patients in all, with 225 being homozygous, 90 having novel variants, and 9 having copy number variations. MPS IV was the most prevalent type (34.8%), followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin study revealed a distribution trend for common variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]).

Conclusion: This large patient cohort exposes the genetic and regional topography of MPS in Iran, providing insight into the disease's genetic epidemiology and allowing for a more cost-effective and timely diagnosis method based on region-specific variants.

Keywords: MPS, copy number variation, geographical distribution, lysosomal storage disorders, mucopolysaccharidosis, single nucleotide variant, targeted next-generation sequencing