| 1. |
- Abel, Olubunmi, et al.
(författare)
-
ALSoD : A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics
- 2012
-
Ingår i: Human Mutation. - Hoboken, NJ : Wiley-Blackwell. - 1059-7794 .- 1098-1004. ; 33:9, s. 1345-1351
-
Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is the commonest adult onset motor neuron disease, with a peak age of onset in the seventh decade. With advances in genetic technology, there is an enormous increase in the volume of genetic data produced, and a corresponding need for storage, analysis, and interpretation, particularly as our understanding of the relationships between genotype and phenotype mature. Here, we present a system to enable this in the form of the ALS Online Database (ALSoD at http://alsod.iop.kcl.ac.uk), a freely available database that has been transformed from a single gene storage facility recording mutations in the SOD1 gene to a multigene ALS bioinformatics repository and analytical instrument combining genotype, phenotype, and geographical information with associated analysis tools. These include a comparison tool to evaluate genes side by side or jointly with user configurable features, a pathogenicity prediction tool using a combination of computational approaches to distinguish variants with nonfunctional characteristics from disease-associated mutations with more dangerous consequences, and a credibility tool to enable ALS researchers to objectively assess the evidence for gene causation in ALS. Furthermore, integration of external tools, systems for feedback, annotation by users, and two-way links to collaborators hosting complementary databases further enhance the functionality of ALSoD. Hum Mutat 33:1345-1351, 2012. (c) 2012 Wiley Periodicals, Inc.
|
|
| 2. |
- Ain, Noor U., et al.
(författare)
-
Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature
- 2020
-
Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 42:1, s. 89-101
-
Tidskriftsartikel (refereegranskat)abstract
- Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (<-8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.
|
|
| 3. |
- Ali, Heidi, et al.
(författare)
-
Classification of mismatch repair gene missense variants with PON-MMR
- 2012
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 33:4, s. 642-650
-
Tidskriftsartikel (refereegranskat)abstract
- Numerous mismatch repair (MMR) gene variants have been identified in Lynch syndrome and other cancer patients, but knowledge about their pathogenicity is frequently missing. The diagnosis and treatment of patients would benefit from knowing which variants are disease related. Bioinformatic approaches are well suited to the problem and can handle large numbers of cases. Functional effects were revealed based on literature for 168 MMR missense variants. Performance of numerous prediction methods was tested with this dataset. Among the tested tools, only the results of tolerance prediction methods correlated to functional information, however, with poor performance. Therefore, a novel consensus-based predictor was developed. The novel prediction method, pathogenic-or-not mismatch repair (PON-MMR), achieved accuracy of 0.87 and Matthews correlation coefficient of 0.77 on the experimentally verified variants. When applied to 616 MMR cases with unknown effects, 81 missense variants were predicted to be pathogenic and 167 neutral. With PON-MMR, the number of MMR missense variants with unknown effect was reduced by classifying a large number of cases as likely pathogenic or benign. The results can be used, for example, to prioritize cases for experimental studies and assist in the classification of cases. Hum Mutat 33:642650, 2012. (c) 2012 Wiley Periodicals, Inc.
|
|
| 4. |
- Andersson, Nadine G, et al.
(författare)
-
Novel F8 and F9 gene variants from the PedNet Hemophilia Registry classified according to ACMG/AMP guidelines
- 2020
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 41:12, s. 2058-2072
-
Tidskriftsartikel (refereegranskat)abstract
- In hemophilia A and B, analysis of the F8 and F9 gene variants enables carrier- and prenatal diagnosis and prediction of risk for development of inhibitors. The PedNet Registry collects clinical, genetic and phenotypic data prospectively on >2000 children with hemophilia. The genetic reports of F8/F9 gene variants were classified uniformly to HGVS nomenclature and re-evaluated using international population- and disease-specific databases, literature survey and, where applicable, computational predictive programs. We report 88 novel variants in the F8 and F9 genes, 80 fulfilling criteria for class 5 (pathogenic), six for class 4 (likely pathogenic) and two fulfilling criteria for class 3 (variant of unknown significance) of the ACMG (American College of Medical Genetics and Genomics)/AMP (Association for Molecular Pathology) guidelines together with information on the respective phenotype and inhibitor formation. The study highlights the need to re-evaluate and update earlier genetic reports in hemophilia both locally but also in variant databases in the light of changed nomenclature and new guidelines. This article is protected by copyright. All rights reserved.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Ballantyne, Kaye N., et al.
(författare)
-
Toward Male Individualization with Rapidly Mutating Y-Chromosomal Short Tandem Repeats
- 2014
-
Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 35:8, s. 1021-1032
-
Tidskriftsartikel (refereegranskat)abstract
- Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, greater than99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RMY-STRs in identifying and separating unrelated and related males and provides a reference database.
|
|
| 8. |
|
|
| 9. |
- Bento, Celeste, et al.
(författare)
-
Genetic Basis of Congenital Erythrocytosis : Mutation Update and Online Databases
- 2014
-
Ingår i: Human Mutation. - : Wiley-Blackwell. - 1059-7794 .- 1098-1004. ; 35:1, s. 15-26
-
Tidskriftsartikel (refereegranskat)abstract
- Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.
|
|
| 10. |
|
|
