Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with mucopolysaccharidoses type I and type <scp>II</scp>

Uttarilli, Anusha; Ranganath, Prajnya; Matta, Divya; Jain, Jamal Md Nurul; Prasad, Krishna; Babu, A.S.; Girisha, Katta M.; Verma, Ishwar C.; Phadke, Shubha R.; Mandal, Kausik; Puri, Ratna Dua; Aggarwal, Shagun; Danda, Sumita; Sankar, V.H.; Kapoor, Seema; Bhat, Meenakshi; Gowrishankar, Kalpana; Hasan, Annie Q.; Nair, Mohandas; Nampoothiri, Sheela; Dalal, Ashwin

doi:10.1111/cge.12795

Cited by 24 publications

(21 citation statements)

References 24 publications

(34 reference statements)

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“…ing of IDUA gene have been analyzed in a series of MPSI population in the Iranian population.The detected mutations in our population were very different from other recent studies where sequencing analysis of the IDUA gene was conducted [10][11][12][13][14][15]. Despite sequencing analysis of all 14 exons and exon-intron boundaries of the IDUA gene, genotypes of two patients are still unknown.…”

contrasting

confidence: 79%

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Taghikhani

Khatami

Abdi

et al. 2019

Clinical Laboratory Analysis

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BackgroundMucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by a deficiency of α‐l‐iduronidase (IDUA) encoded by the IDUA gene. We examined the mutation spectrum of the IDUA gene to explain the clinical, biochemical, and molecular features in 21 Iranian patients with MPSI.MethodsSanger sequencing was used to measure the IDUA gene sequence in the coding region and exon‐intron boundaries. We recorded the clinical findings of studied patients at the first diagnosis of disease and then during the treatment and follow‐up.ResultsFive different missense disease‐causing mutations were determined in our patient groups, indicating 90.48% of detection rate. The most widespread mutation was the p.Y109H, occurring in 15.625% of all alleles, which was reported for the first time in our study. Other frequent mutations were as follows: p.Ser157Pro (12.5%), p.Gly84Arg (12.5%), p.Asp257His (9.375%), and p.Asp301Glu (9.375%). Three ones of them were new missense mutations: p.Ser157Pro, p.Asp257His, and p.Asp301Glu.DiscussionThe results of this study explain the different spectrum of IDUA gene mutations in our patients with MPSI. We introduced here 32 different variants including four new variants: p.Y109H (15.625%), p.S157P (12.5%), p.D257H (9.375%), and p.D301E (9.375%). In this series, there was no relationship between the happening of clinical features and genotype variations and biochemical findings.

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contrasting

confidence: 79%

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Taghikhani

Khatami

Abdi

et al. 2019

Clinical Laboratory Analysis

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“…Interestingly, a complex rearrangement (IDS inversion) was found in four unrelated patients, in whom one case was referred from the NBS program for MPS. The pseudogene (I2S2/IDSP1) located on the telomeric side of IDS has been shown to undergo homologous recombination leading to large complex genomic/genetic rearrangements, which comprise about 13% of mutations [10,36]. Patients with this mutation had the attenuated phenotype.…”

Section: Discussionmentioning

confidence: 99%

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

Lin

Chern

et al. 2019

IJMS

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Hunter syndrome (mucopolysaccharidosis II; MPS II) is caused by a defect of the iduronate-2-sulfatase (IDS) gene. Few studies have reported integrated mutation data of Taiwanese MPS II phenotypes. In this study, we summarized genotype and phenotype correlations of confirmed MPS II patients and asymptomatic MPS II infants in Taiwan. Regular polymerase chain reaction and DNA sequencing were used to identify genetic abnormalities of 191 cases, including 51 unrelated patients with confirmed MPS II and 140 asymptomatic infants. IDS activity was analyzed in individual novel IDS variants using in vitro expression studies. Nineteen novel mutations were identified, in which the percentages of IDS activity of the novel missense mutations c.and c.1403G>A were significantly decreased (p < 0.001), c.254C>T and c.1025A>G were moderately decreased (p < 0.01), and c.851C>T was slightly decreased (p < 0.05) comparing with normal enzyme activity. The activities of the other six missense mutations were reduced but were insignificant. The results of genomic studies and their phenotypes were highly correlated. A greater understanding of the positive correlations may help to prevent the irreversible manifestations of Hunter syndrome, particularly in infants suspected of having asymptomatic MPS II. In addition, urinary glycosaminoglycan assay is important to diagnose Hunter syndrome since gene mutations are not definitive (could be non-pathogenic).Sequencing data were obtained by scanning through the data to identify anomalies using Applied Biosystems Sequence Scanner Software v2.0 Sequence Trace Viewer and Editor (Applied Biosystems Co., CA, USA) and manual progressive alignment. A total of 51 mutations of the IDS gene from the 191 cases, including the confirmed patients (n = 51) and infants suspected of having MPS II (n = 140) that were identified. The suspected MPS II infants were classified into two groups: Those with either 1) "positive" uGAG biochemistry examinations, reduction in leukocyte IDS enzyme activity, and identified IDS variations (n = 7); or 2) "negative" uGAG biochemistry examinations, reduction in leukocyte IDS enzyme activity and identified IDS variations (n = 133). The 51 mutations of the IDS gene included 32 missense (62.7%), 3 nonsense (5.9%), 2 silent (3.9%), 6 splicing (11.8%), 4 small deletions (7.8%), 3 gross deletions (5.9%), and 1 complex inversion (2%) ( Table 1). Of these mutations, 35 were reported and verified as being pathogenic for MPS II with varying degrees of severity or non-pathogenic , and the other 16 were novel mutations (Figure 1), which needed to be verified according to individual IDS activity by using in vitro expression studies.

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“…MPS I is caused by mutations in the gene encoding IDUA, which is located on chromosome 4p16.3 [35, 36]. The birth prevalence of MPS I is higher in Northern European countries such as Norway (accounts for 60% of all MPS), Demark, Sweden [16], and Northern Ireland [18].…”

Section: Methodsmentioning

confidence: 99%

Epidemiology of mucopolysaccharidoses

Khan

Peracha

Ballhausen³

et al. 2017

Molecular Genetics and Metabolism

320

239

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The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34 years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low.

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Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with mucopolysaccharidoses type I and type II

Cited by 24 publications

References 24 publications

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

Epidemiology of mucopolysaccharidoses

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