Phenotype-oriented NGS panels for mucopolysaccharidoses: Validation and potential use in the diagnostic flowchart

Brusius-Facchin, Ana Carolina; Siebert, Marina; Leão, Delva Pereira; Málaga, Diana Rojas; Pasqualim, Gabriela; Trapp, Franciele Barbosa; Matte, Úrsula da Silveira; Giugliani, Roberto; Leistner-Segal, Sandra

doi:10.1590/1678-4685-gmb-2018-0102

Cited by 13 publications

(16 citation statements)

References 25 publications

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“…This DBS sample was also analyzed by next-generation sequencing (NGS) on the Ion S5 System platform (Thermo Scientific™, Waltham, MA, USA) employing a customized and validated panel (Ion AmpliSeq™ Thermo Scientific™), including the IDUA gene [ 36 ].…”

Section: Methods and Resultsmentioning

confidence: 99%

Neonatal Screening for MPS Disorders in Latin America: A Survey of Pilot Initiatives

Kubaski

Sousa

Amorim

et al. 2020

IJNS

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Newborn screening enables the diagnosis of treatable disorders at the early stages, and because of its countless benefits, conditions have been continuously added to screening panels, allowing early intervention, aiming for the prevention of irreversible manifestations and even premature death. Mucopolysaccharidoses (MPS) are lysosomal storage disorders than can benefit from an early diagnosis, and thus are being recommended for newborn screening. They are multisystemic progressive disorders, with treatment options already available for several MPS types. MPS I was the first MPS disorder enrolled in the newborn screening (NBS) panel in the USA and a few other countries, and other MPS types are expected to be added. Very few studies about NBS for MPS in Latin America have been published so far. In this review, we report the results of pilot studies performed in Mexico and Brazil using different methodologies: tandem mass spectrometry, molecular analysis, digital microfluidics, and fluorimetry. These experiences are important to report and discuss, as we expect to have several MPS types added to NBS panels shortly. This addition will enable timely diagnosis of MPS, avoiding the long diagnostic odyssey that is part of the current natural history of this group of diseases, and leading to a better outcome for the affected patients.

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Section: Methods and Resultsmentioning

confidence: 99%

Neonatal Screening for MPS Disorders in Latin America: A Survey of Pilot Initiatives

Kubaski

Sousa

Amorim

et al. 2020

IJNS

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“…One of the advantages of this approach, compared to whole-exome and whole-genome analysis, is that less effort in terms of bioinformatics and computational power is required, since a significantly lesser amount of data is analyzed. The previous results of three custom panels designed to amplify the coding regions of 11 MPS-associated genes demonstrated the high sensitivity and specificity of a TNGS approach to mutation identification when compared to the gold standard (Sanger sequencing), leading to the detection of 250 variants and a 90% breadth of coverage of the targets [7].…”

Section: Molecular Genetics Analysesmentioning

confidence: 99%

“…The correct diagnosis enables specific therapeutic measures (available for most MPS patients) to be taken, and also phenotype prediction, carrier identification, genetic counseling, and prenatal diagnosis. As therapy outcomes seem to be better when the disease is identified early in life, screening for MPS in high-risk groups and even newborn screening programs for selected MPS types are taking place [2,[4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of Mucopolysaccharidoses

et al. 2020

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The mucopolysaccharidoses (MPSs) include 11 different conditions caused by specific enzyme deficiencies in the degradation pathway of glycosaminoglycans (GAGs). Although most MPS types present increased levels of GAGs in tissues, including blood and urine, diagnosis is challenging as specific enzyme assays are needed for the correct diagnosis. Enzyme assays are usually performed in blood, with some samples (as leukocytes) providing a final diagnosis, while others (such as dried blood spots) still being considered as screening methods. The identification of variants in the specific genes that encode each MPS-related enzyme is helpful for diagnosis confirmation (when needed), carrier detection, genetic counseling, prenatal diagnosis (preferably in combination with enzyme assays) and phenotype prediction. Although the usual diagnostic flow in high-risk patients starts with the measurement of urinary GAGs, it continues with specific enzyme assays and is completed with mutation identification; there is a growing trend to have genotype-based investigations performed at the beginning of the investigation. In such cases, confirmation of pathogenicity of the variants identified should be confirmed by measurement of enzyme activity and/or identification and/or quantification of GAG species. As there is a growing number of countries performing newborn screening for MPS diseases, the investigation of a low enzyme activity by the measurement of GAG species concentration and identification of gene mutations in the same DBS sample is recommended before the suspicion of MPS is taken to the family. With specific therapies already available for most MPS patients, and with clinical trials in progress for many conditions, the specific diagnosis of MPS as early as possible is becoming increasingly necessary. In this review, we describe traditional and the most up to date diagnostic methods for mucopolysaccharidoses.

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“…In our experience, caution must be taken when performing NGS for IDUA due to its high G-C content, which may result in lower coverage, especially for Exons 1 (78% G-C content), 9 (77%), and 10 (74%). However, validation of a gene-targeted panel for MPS showed high sensitivity and specificity [64]. Variant prioritization should be performed by someone with experience in MPS I.…”

Section: Molecular Diagnosismentioning

confidence: 99%

Mucopolysaccharidosis Type I

et al. 2020

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Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as Hurler syndrome, the intermediate form as Hurler–Scheie, and the most attenuated form is known as Scheie syndrome. Phenotype seems to be largely influenced by genotype. Patients usually develop several somatic symptoms such as abdominal hernias, extensive dermal melanocytosis, thoracolumbar kyphosis odontoid dysplasia, arthropathy, coxa valga and genu valgum, coarse facial features, respiratory and cardiac impairment. The diagnosis is based on the quantification of α-l-iduronidase coupled with glycosaminoglycan analysis and gene sequencing. Guidelines for treatment recommend hematopoietic stem cell transplantation for young Hurler patients (usually at less than 30 months of age). Intravenous enzyme replacement is approved and is the standard of care for attenuated—Hurler–Scheie and Scheie—forms (without cognitive impairment) and for the late-diagnosed severe—Hurler—cases. Intrathecal enzyme replacement therapy is under evaluation, but it seems to be safe and effective. Other therapeutic approaches such as gene therapy, gene editing, stop codon read through, and therapy with small molecules are under development. Newborn screening is now allowing the early identification of MPS I patients, who can then be treated within their first days of life, potentially leading to a dramatic change in the disease’s progression. Supportive care is very important to improve quality of life and might include several surgeries throughout the life course.

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Phenotype-oriented NGS panels for mucopolysaccharidoses: Validation and potential use in the diagnostic flowchart

Cited by 13 publications

References 25 publications

Neonatal Screening for MPS Disorders in Latin America: A Survey of Pilot Initiatives

Neonatal Screening for MPS Disorders in Latin America: A Survey of Pilot Initiatives

Diagnosis of Mucopolysaccharidoses

Mucopolysaccharidosis Type I

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