Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations

Pollard, Laura; Jones, Julie R.; Wood, Tim

doi:10.1007/s10545-012-9533-7

Cited by 55 publications

(39 citation statements)

References 37 publications

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“…(Arg468Gln)ClinVar ID:10498[71]Pathogenicc.1478G>Cp. (Arg493Pro)–[46]Likely pathogenicc.1563A>Tp. (Glu521Asp)–NovelLikely pathogenicDeletion of the whole IDS gene––[56]PathogenicHomologous recombination IDS-IDS2––[36]PathogenicDeletion ex 1–7 (2 deletions in tandem with 2 duplications 1.2 Mb distally to IDS gene)––[74]Pathogenic SGSH (NM_000199.4; NP_000190.1)c.118T>Ap.…”

Section: Resultsmentioning

confidence: 99%

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Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

et al. 2019

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Mucopolysaccharidoses (MPS) are a subgroup of 11 monogenic lysosomal storage disorders due to the deficit of activity of the lysosomal hydrolases deputed to the degradation of mucopolysaccharides. Although individually rare, all together they account for at least 1:25,000 live births. In this study, we present the genetic analysis of a population of 71 MPS patients enrolled in a multicenter Italian study. We re-annotated all variants, according to the latest recommendations, and re-classified them as suggested by the American College of Medical Genetics and Genomics. Variant distribution per type was mainly represented by missense mutations. Overall, 10 patients had received no molecular diagnosis, although 6 of them had undergone either HSCT or ERT, based on clinical and enzymatic evaluations. Moreover, nine novel variants are reported. Conclusions : Our analysis underlines the need to complete the molecular diagnosis in patients previously diagnosed only on a biochemical basis, suggests a periodical re-annotation of the variants and solicits their deposition in public databases freely available to clinicians and researchers. We strongly recommend a molecular diagnosis based on the analysis of the “trio” instead of the sole proband. These recommendations will help to obtain a complete and correct diagnosis of mucopolysaccharidosis, rendering also possible genetic counseling. What is known • MPS are a group of 11 metabolic genetic disorders due to deficits of enzymes involved in the mucopolysaccharides degradation. • Molecular analysis is commonly performed to confirm enzymatic assays. What is new • Eighty-six percent of the 71 patients we collected received a molecular diagnosis; among them, 9 novel variants were reported. • We stress the importance of molecular diagnosis in biochemically diagnosed patients, encourage a periodical re-annotation of variants according to the recent nomenclature and their publication in open databases. Electronic supplementary material The online version of this article (10.1007/s00431-019-03341-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…(Arg468Gln)Severe (P20)Severe [71]; severe [57]; severe [67]; four severe patients [63]; severe [34]; three severe patients [35]; severe [31]; severe [25]; severe [18]c.1478G>Cp. (Arg493Pro)Severe (P17)Phenotype not reported [46]SGSHc.197C>Gp. (Ser66Trp)Severe (P27)Two severe, three intermediate, one unknown [17]c.220C>Tp.…”

Section: Resultsmentioning

confidence: 99%

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

et al. 2019

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“…It includes the major mutation types that were previously described in larger MPSII series and nine small and ‘private’ novel changes, one novel exon 1 deletion or c.(−217_103del), one unknown splicing defect, one chimeric IDS‐IDSP1 allele and four complete IDS / IDSP1 deletions that were delineated using microarray analysis (Table ). The four point mutations that occur at CpG dinucleotides identified in this study (4/10; 40%) are highly recurring C > T or G > A transitions in the MPSII cases according to LOVD and HGMD registries; thus, they are considered to be ‘hot spots’ . This proportion of C > T or G > A transitions at CpG dinucleotides is consistent with 47% of the previously reported pathogenic variants at IDS .…”

Section: Discussionmentioning

confidence: 99%

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

et al. 2016

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Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.

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“…An examination of patients with Hunter syndrome showed that exon 3 of the IDS gene had significantly more mutations than that of other exons [8]. The patients with MPS II have a wide range of symptoms caused by the disease affecting multiple different organ systems.…”

Section: Introductionmentioning

confidence: 99%

Growth charts for patients with Hunter syndrome

Patel

Suzuki

Maeda

et al. 2014

Molecular Genetics and Metabolism Reports

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Children with mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, an X-linked disorder, suffer from a multisystem dysfunction caused by the accumulation of glycosaminoglycans. However, there has been no systemic report on the growth of patients with MPS II. The purpose of this study is to describe the growth patterns of patients with MPS II and to compare with the patterns of age-matched controls. Data (height, weight, age, etc.) was collected in a longitudinal study of Japanese male patients with MPS II (n = 111). The mean birth length was 50.31 ± 1.42 cm, while the mean birth weight was 3.35 ± 0.39 kg. The mean final height and weight at 18 years and older were 125.63 ± 9.09 cm and 37.18 ± 8.72 kg; corresponding to a difference of − 46.40 cm and − 25.89 kg lower, when compared with healthy Japanese male controls. The mean birth BMI was 10.84 ± 3.29 kg/m2, while the mean BMI at 18 years was 29.41 ± 6.15 kg/m2. The growth pattern in patients with MPS II was characterized by overgrowth for the first several years, although growth velocity fell below that of the normal healthy controls after one year of age. No statistical difference in height was observed between patients with the attenuated and severe phenotypes in each age class.In conclusion, this report describes the natural history of growth in patients with MPS II, which can help in monitoring the progression of the disease as well as assessing therapeutic efficacy.

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Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations

Cited by 55 publications

References 37 publications

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

Growth charts for patients with Hunter syndrome

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