scholarly journals Which Is the Best In Silico Program for the Missense Variations in IDUA Gene? A Comparison of 33 Programs Plus a Conservation Score and Evaluation of 586 Missense Variants

2021 ◽  
Vol 8 ◽  
Author(s):  
Pâmella Borges ◽  
Gabriela Pasqualim ◽  
Ursula Matte
Keyword(s):  
Literature Review ◽  
Conservation Score ◽  
Type I ◽  
Variants Of Unknown Significance ◽  
Mutation Database ◽  
Unknown Significance ◽  
Kappa Value ◽  
Idua Gene ◽  
Sensitivity Specificity ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease characterized by the deficiency of alpha-L-iduronidase (IDUA), an enzyme involved in glycosaminoglycan degradation. More than 200 disease-causing variants have been reported and characterized in the IDUA gene. It also has several variants of unknown significance (VUS) and literature conflicting interpretations of pathogenicity. This study evaluated 586 variants obtained from the literature review, five population databases, in addition to dbSNP, Human Genome Mutation Database (HGMD), and ClinVar. For the variants described in the literature, two datasets were created based on the strength of the criteria. The stricter criteria subset had 108 variants with expression study, analysis of healthy controls, and/or complete gene sequence. The less stringent criteria subset had additional 52 variants found in the literature review, HGMD or ClinVar, and dbSNP with an allele frequency higher than 0.001. The other 426 variants were considered VUS. The two strength criteria datasets were used to evaluate 33 programs plus a conservation score. BayesDel (addAF and noAF), PON-P2 (genome and protein), and ClinPred algorithms showed the best sensitivity, specificity, accuracy, and kappa value for both criteria subsets. The VUS were evaluated with these five algorithms. Based on the results, 122 variants had total consensus among the five predictors, with 57 classified as predicted deleterious and 65 as predicted neutral. For variants not included in PON-P2, 88 variants were considered deleterious and 92 neutral by all other predictors. The remaining 124 did not obtain a consensus among predictors.

scholarly journals Molecular Analysis of Vietnamese Patients with Mucopolysaccharidosis Type I

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1162
Author(s):  
Ngoc Thi Bich Can ◽  
Dien Minh Tran ◽  
Thao Phuong Bui ◽  
Khanh Ngoc Nguyen ◽  
Hoang Huy Nguyen ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Direct Dna Sequencing ◽  
Pathogenic Variants ◽  
Vietnamese Population ◽  
Idua Gene ◽  
Classical Characteristic ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by deleterious mutations in the α‑L‑iduronidase (IDUA) gene. Until now, MPS I in Vietnamese has been poorly addressed. Five MPS I patients were studied with direct DNA sequencing using Illumina technology confirming pathogenic variants in the IDUA gene. Clinical characteristics, additional laboratory results, and family history were collected. All patients have presented with the classical characteristic of MPS I, and α‑L‑iduronidase activity was low with the accumulation of glycosaminoglycans. Three variants in the IDUA gene (c.1190‑10C>A (Intronic), c.1046A>G (p.Asp349Gly), c.1862G>C (p.Arg621Pro) were identified. The c.1190‑10C>A variant represents six of the ten disease alleles, indicating a founder effect for MPS I in the Vietnamese population. Using biochemical and genetic analyses, the precise incidence of MPS I in this population should accelerate early diagnosis, newborn screening, prognosis, and optimal treatment

Web-Based Bioinformatics Predictors: Recommendations to Assess Lysosomal Cholesterol Trafficking Diseases-Related Genes

2019 ◽  
Vol 58 (01) ◽  
pp. 050-059 ◽  
Author(s):  
Laura López de Frutos ◽  
Jorge J. Cebolla ◽  
Pilar Irún ◽  
Ralf Köhler ◽  
Pilar Giraldo
Keyword(s):  
Genetic Variants ◽  
Lysosomal Storage ◽  
Cholesterol Trafficking ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Deleterious Gene ◽  
The One ◽  
Matthew’S Correlation Coefficient ◽  
Sensitivity Specificity ◽  
The Impact

Introduction The growing number of genetic variants of unknown significance (VUS) and availability of several in silico prediction tools make the evaluation of potentially deleterious gene variants challenging. Materials and Methods We evaluated several programs and software to determine the one that can predict the impact of genetic variants found in lysosomal storage disorders (LSDs) caused by defects in cholesterol trafficking best. We evaluated the sensitivity, specificity, accuracy, precision, and Matthew's correlation coefficient of the most common software. Results Our findings showed that for exonic variants, only MutPred1 reached 100% accuracy and generated the best predictions (sensitivity and accuracy = 1.00), whereas intronic variants, SROOGLE or Human Splicing Finder (HSF) generated the best predictions (sensitivity = 1.00, and accuracy = 1.00). Discussion Next-generation sequencing substantially increased the number of detected genetic variants, most of which were considered to be VUS, creating a need for accurate pathogenicity prediction. The focus of the present study is the importance of accurately predicting LSDs, with majority of previously unreported specific mutations. Conclusion We found that the best prediction tool for the NPC1, NPC2, and LIPA variants was MutPred1 for exonic regions and HSF and SROOGLE for intronic regions and splice sites.

Gene Therapy of Mucopolysaccharidosis Type I Mice: Repeated Administrations and Safety Assessment of pIDUA/Nanoemulsion Complexes

2021 ◽  
Vol 21 ◽  
Author(s):  
Michelle Fraga ◽  
Roselena Silvestri Schuh ◽  
Édina Poletto ◽  
Talita Giacomet de Carvalho ◽  
Raqueli Teresinha França ◽  
...  
Keyword(s):  
Safety Assessment ◽  
Transfection Efficiency ◽  
Signs And Symptoms ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Medium Chain Triglycerides ◽  
Repeated Administrations ◽  
Idua Gene ◽  
Mps I

Background: Mucopolysaccharidosis type I (MPS I) is an inherited disorder caused by α-L-iduronidase (IDUA) deficiency. The available treatments are not effective in improving all signs and symptoms of the disease. Objective: : In the present study, we evaluated the transfection efficiency of repeated intravenous administrations of cationic nanoemulsions associated with the plasmid pIDUA (containing IDUA gene). Methods: Cationic nanoemulsions were composed of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino[polyethylene glycol]-2000) (DSPE-PEG), 1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP), medium chain triglycerides, glycerol, and water and were prepared by high-pressure homogenization and were repeatedly administered to MPS I mice for IDUA production and gene expression. Results: A significant increase in IDUA expression was observed in all organs analyzed, and IDUA activity tended to increase with repeated administrations when compared to our previous report, when mice received a single administration of the same dose. In addition, GAGs were partially cleared from organs, as assessed through biochemical and histology analyzes. There was no presence of inflammatory infiltrate, necrosis, or signs of increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed reduced presence of macrophage cells in treated than in untreated MPS I mice. Conclusion: These set of results suggest that repeated administrations can improve transfection efficiency of cationic complexes without significant increase in toxicity in the MPS I murine model.

Transvaginal Ultrasonography and Saline Infusion Sonography Compared to Hysteroscopy for Diagnosis of Intracavity Lesion: A 4-Year Experience in Suburban Referral Hospital

2020 ◽  
Vol 103 (6) ◽  
pp. 585-593
Keyword(s):  
Predictive Value ◽  
Final Diagnosis ◽  
Saline Infusion ◽  
Transvaginal Ultrasonography ◽  
Histopathological Diagnosis ◽  
Endometrial Polyps ◽  
Saline Infusion Sonography ◽  
Submucous Myoma ◽  
Kappa Value ◽  
Sensitivity Specificity

Objective: To evaluate the accuracy of transvaginal ultrasonography (TVS) and saline infusion sonography (SIS) in use for the diagnosis of endometrial polyps and submucous myoma compared to hysteroscopy. Histopathology was considered as the gold standard for final diagnosis. Materials and Methods: The present retrospective study was conducted at Bhumibol Adulyadej Hospital, Bangkok, Thailand between January 2014 and December 2017. Medical records of 150 patients who attended for hysteroscopy and histopathological diagnosis were reviewed. The accuracy of TVS and SIS for the diagnosis of endometrial polyps and submucous myoma were determined. Results: Out of 150 enrolled cases, endometrial polyp was the most frequent hysteroscopic finding in participants of the present study (92/150). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of TVS, SIS, and hysteroscopy compared to pathologic reports for detection endometrial polyps were 71.7% versus 93.5% versus 97.8%, 38.5% versus 52.2% versus 68.2%, 80.5% versus 88.7% versus 92.8%, 27.8% versus 66.7% versus 88.2%, and 64.4% versus 85.2% versus 92.1%, respectively. The sensitivity, specificity, PPV, NPV, and accuracy of TVS, SIS, and hysteroscopy for detection of submucous myoma were 81.6% versus 92.1% versus 94.7%, 66.7% versus 86.9% versus 100%, 77.5% versus 92.1% versus 100%, 72.0% versus 86.9% versus 90.9%, and 75.4% versus 90.2% versus 96.6%, respectively. The kappa value from TVS, SIS, and hysteroscopy when the histopathologic reports were overall intrauterine abnormalities, endometrial polyps and submucous myoma were 0.45/0.43/0.72, 0.77/0.76/0.89, and 0.92/0.92/1.00, respectively. Conclusion: Sensitivity, specificity, PPV, NPV, accuracy, and kappa value of SIS for detecting endometrial polyps and submucous myoma were better than TVS. Keywords: Ultrasonography, Saline infusion sonography, Hysteroscopy, Accuracy

scholarly journals Sexual behaviour in a murine model of mucopolysaccharidosis type I (MPS I)

PLoS ONE ◽  
2019 ◽  
Vol 14 (12) ◽  
pp. e0220429 ◽  
Author(s):  
Ana Barbosa Mendes ◽  
Cinthia Castro do Nascimento ◽  
Vânia D’Almeida
Keyword(s):  
Sexual Behaviour ◽  
Murine Model ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Mps I

scholarly journals Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance

2017 ◽  
Vol 10 (5) ◽  
Author(s):  
Bian Li ◽  
Jeffrey L. Mendenhall ◽  
Brett M. Kroncke ◽  
Keenan C. Taylor ◽  
Hui Huang ◽  
...  
Keyword(s):  
Functional Impact ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

scholarly journals Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T)

2016 ◽  
Vol 18 (1) ◽  
pp. 93-103
Author(s):  
Daniela Alosi ◽  
Marie Bisgaard ◽  
Sophie Hemmingsen ◽  
Lotte Krogh ◽  
Hanne Mikkelsen ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Gene Variants ◽  
Analysis Method ◽  
Variants Of Unknown Significance ◽  
Significance Analysis ◽  
Unknown Significance

scholarly journals Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
A. Chin ◽  
S. Balasubramanyam ◽  
C. M. Davis
Keyword(s):  
Autosomal Dominant ◽  
Severe Infection ◽  
Severe Atopic Dermatitis ◽  
Genomic Testing ◽  
Atopic Diseases ◽  
Variants Of Unknown Significance ◽  
Hyper Ige Syndrome ◽  
Heterozygous Variant ◽  
Unknown Significance ◽  
Multiple Variants

Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. The discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease.

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