Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1
-
Muhammad Yasir Zahoor
,
Huma Arshad Cheema
Abstract
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.
Funding source: Higher Education Commission
Award Identifier / Grant number: 6948/NRPU/HEC/2017
Funding statement: This research was supported by the Higher Education Commission, Pakistan (Funder Id: http://dx.doi.org/10.13039/501100004681, Project No. 6948/NRPU/HEC/2017).
Acknowledgments
The authors would like to thank the families for participating in the study and Centogene AG, Germany, for facilitation in molecular diagnosis of some patients.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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©2019 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Hypo- and hyperthyroidism in early life – new developments
- Letters to the Editor
- Optic nerve sheath diameter appraisal in children affected by diabetic ketoacidosis
- Optic nerve sheath diameter ultrasound measurement to evaluate cerebral edema in children with diabetic ketoacidosis
- Original Articles
- Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy
- Phenylketonuric patients represent their disease
- Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1
- Genetic testing of two Pakistani patients affected with rare autosomal recessive Fanconi-Bickel syndrome and identification of a novel SLC2A2 splice site variant
- Sex differences in infant body composition emerge in the first 5 months of life
- Characterization of the duration of treatment with diazoxide in infants with prolonged hyperinsulinism (PHI)
- Clinical, biochemical and gender characteristics of 97 prepubertal children with premature adrenarche
- The adjustment of 17-hydroxyprogesterone cut-off values for congenital adrenal hyperplasia neonatal screening by GSP according to gestational age and age at sampling
- The role of vitamin D replacement therapy in serum FGF23 concentration in children with myelomeningocele compared with healthy children – a preliminary study
- Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism
- Congenital hypothyroidism in preterm infants: a 3- to 8-year longitudinal study in southern Thailand
- Case Reports
- A case of PHACE syndrome with growth hormone deficiency and abnormal thyroid functions
- A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature
- Acquired von Willebrand’s syndrome caused by primary hypothyroidism in a 5-year-old girl
- Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report
Articles in the same Issue
- Frontmatter
- Editorial
- Hypo- and hyperthyroidism in early life – new developments
- Letters to the Editor
- Optic nerve sheath diameter appraisal in children affected by diabetic ketoacidosis
- Optic nerve sheath diameter ultrasound measurement to evaluate cerebral edema in children with diabetic ketoacidosis
- Original Articles
- Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy
- Phenylketonuric patients represent their disease
- Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1
- Genetic testing of two Pakistani patients affected with rare autosomal recessive Fanconi-Bickel syndrome and identification of a novel SLC2A2 splice site variant
- Sex differences in infant body composition emerge in the first 5 months of life
- Characterization of the duration of treatment with diazoxide in infants with prolonged hyperinsulinism (PHI)
- Clinical, biochemical and gender characteristics of 97 prepubertal children with premature adrenarche
- The adjustment of 17-hydroxyprogesterone cut-off values for congenital adrenal hyperplasia neonatal screening by GSP according to gestational age and age at sampling
- The role of vitamin D replacement therapy in serum FGF23 concentration in children with myelomeningocele compared with healthy children – a preliminary study
- Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism
- Congenital hypothyroidism in preterm infants: a 3- to 8-year longitudinal study in southern Thailand
- Case Reports
- A case of PHACE syndrome with growth hormone deficiency and abnormal thyroid functions
- A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature
- Acquired von Willebrand’s syndrome caused by primary hypothyroidism in a 5-year-old girl
- Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report
