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

Abstract

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM‐targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non‐MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent 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]). Our extensive patient cohort reveals the genetic and geographic landscape of 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.

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases

“…CNVs in MPS-related genes have been characterized and encompass: (i) deletion of exon 14-3′UTR, and duplication of exon 2-intron 12 in IDUA in patients affected by MPS I [ 42 , 43 ]; (ii) deletion of SGSH exons 1–5 in MPS IIIA patients [ 44 ]; (iii) Alu -mediated deletion of NAGLU exons 3–4 in patients with MPS IIIB/Sanfilippo type B syndrome [ 45 , 46 ]; (iv) heterozygous deletion of exon 15 [ 47 ] and homozygous deletion of exons 9–10 in HGSNAT in MPS IIIC or Sanfilippo type C patients [ 43 ]; (v) deletions of GNS exon 1, 2–3, 6–7, 9–14 in patients affected by MPS IIID/Sanfilippo disease type D [ 48 , 49 ]; (vi) deletion of multiple contiguous exons including 1–3, 2–4, 2–5, 3–14, 5–8, 9–14, 10–14, 11–12, and single exon 5 and 13 of GALNS in patients with MPS IVA/Morquio A [ 43 , 50 , 51 , 52 , 53 ]; (vii) ARSB deletion of exons 2–3, exon 4 and exon 5 MPS VI patients [ 54 , 55 , 56 ].…”