Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1.
PMID 31473686 | DOI 10.1515/jpem-2019-0188 · Journal of pediatric endocrinology & metabolism : JPEM · 2019 · View on PubMed ↗
Background Mucopolysaccharidosis type 1 (MPS1) is a rare debilitating multisystem lysosomal disorder resulting due to the deficiency of α-L-iduronidase enzyme (IDUA), caused by recessive mutations in the IDUA gene. Lack or improper amount of the IDUA enzyme results in the improper metabolism of mucopolysaccharides or glycosaminoglycans (GAGs). These large sugar molecules accumulate in lysosomes within cells leading to different systemic complications. The estimated global incidence of MPS1 is 1:100,000 live births for the Hurler and 1:800,000 for the Scheie phenotypes. Methods Thirteen MPS1-affected children from 12 unrelated cohorts were enrolled. All coding and flanking regions of the IDUA gene were sequenced. Bioinformatics tools were used for data analysis and protein prediction for clinical correlations. Results Six IDUA gene mutations were mapped co-segregating with the recessive pattern of inheritance including a novel variant. A novel missense variant c.908T > C (p.L303P) was mapped in two affected siblings in a cohort in the homozygous form. The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs*55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each. Conclusions Multisystem disorders and a wide range of clinical presentation impede the evaluation of patients as well as make it difficult to differentiate between different phenotypes of MPS. Early and accurate diagnosis is crucial for the disease management and implementation of an expanded new-born genetic screening program for inborn errors of metabolism including MPS1. We recommend c.784delC (p.H262Tfs*55) and c.1469T > C (p.L490P) as first-line genetic markers for the molecular diagnosis of MPS1 in Pakistan.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | IDUA | “Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1.” | 0.98 | hgnc_dict_v1 |
| phenotype | mucopolysaccharidosis | “Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | inborn error of metabolism | “Early and accurate diagnosis is crucial for the disease management and implementation of an expanded new-born genetic screening program for inborn errors of metabolism including MPS1.” | 0.93 | phenotype_alias_lexicon_v2 |
| variant | p.L303P | “A novel missense variant c.908T > C (p.L303P) was mapped in two affected siblings in a cohort in the homozygous form.” | 0.95 | hgvs_regex_v1 |
| variant | p.L490P | “The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs*55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each.” | 0.95 | hgvs_regex_v1 |
| variant | c.784delC | “The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs*55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each.” | 0.95 | hgvs_regex_v1 |
| variant | p.H262Tfs | “The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs*55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each.” | 0.95 | hgvs_regex_v1 |
| variant | p.P533R | “The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs*55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each.” | 0.95 | hgvs_regex_v1 |
| variant | p.R105Q | “The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs*55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each.” | 0.95 | hgvs_regex_v1 |