Improving the Assessment of the Outcome of Nonsynonymous SNVs with a Consensus Deleteriousness Score, Condel

González-Pérez, Abel

doi:10.1016/j.ajhg.2011.03.004

Cited by 719 publications

(625 citation statements)

References 38 publications

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“…[29][30][31] The Consensus Deleteriousness software, which combines information derived from SIFT, Polyphen-2, and Mutation Assessor, was used to predict the functionality of nonsynonymous mutations. 32 In addition, we calculated the Combined Annotation Dependent Depletion score (http:// cadd.gs.washington.edu/score), which is another predictor for the pathogenicity of an amino acid change and includes the previous prediction models. 33 …”

Section: Review Materials and Methodsmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a heterotetramer protein complex consisting of four subunits encoded by nuclear genes. These include SDHA and SDHB, which form the catalytic domain, and SDHC and SDHD, which anchor the complex to the inner mitochondrial membrane. 1 The assembly factors, SDHAF1 and SDHAF2, ensure both structural and functional integrity of the complex. 2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate. 1 The TCA cycle is central to the metabolism of sugars, lipids, and amino acids and is a major source of adenosine triphosphate in cells. In addition, the cycle also seems to be involved in tumorigenesis; enzymes of the TCA cycle are involved in the pathogenesis of several tumor types. SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. 12-14 The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α. This results in activation of the hypoxia pathway, which supports tumor formation by activating angiogenesis, glucose metabolism, cell motility, and cell survival. Furthermore, defects in these enzymes lead to epigenetic alterations through an accumulation of oncometabolites inhibiting α-ketoglutarate-dependent dioxygenases, which are involved in DNA and histone demethylation. In addition to SDH-associated tumorigenesis, constitutional complex II deficiencies caused by SDHA, SDHB, SDHD, and SDHAF1 mutations may also lead to Leigh syndrome, infantile leukodystrophies, and cardiomyopathy. 3,[17][18][19] In the current review, our aim is to report all currently known SDH mutations and define their nature and spectrum in SDHrelated tumors, including PCCs/PGLs, GISTs, RCCs, and PAs, as well as in other unusual tumors arising in SDH mutation carriers. We performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor and compared the results with those of SDHA/SDHB immunohistochemistry (IHC) to predict the functional impact of nonsynonymous mutations. Finally, we explored and report here the nature of the second hit in all tumors arising in the SDH deficiency setting. The tricarboxylic acid, or Krebs, cycle is cent...

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Section: Review Materials and Methodsmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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“…I-Mutant2.0 28 was used as a predictor of protein stability changes upon variations. Computational prediction of disease-related variants was performed with the consensus tools CONDEL 29 (combines Logre, MAPP, Massessor, Pph2 and SIFT), Meta-SNP 30 (combines PANTHER, PhD-SNP, SIFT and SNAP), PredictSNP 31 (combines MAPP, PhD-SNP, Pph1, Pph2, SIFT and SNAP) and PON-P2. 32 …”

Section: Bioinformatics Tools For Sequence Variant Interpretationmentioning

confidence: 99%

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

et al. 2016

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SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T4C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/ phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies.

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“…To distinguish variants from local polymorphisms between 200 and 248 anonymized in‐house normal control blood samples were sequenced over the positions of interest. Variant were interpreted for their deleteriousness by using SIFT (Sorting Intolerant From Tolerant), PolyPhen‐2, (Polymorphism Phenotyping version 2), Mutation Taster, Condel (CONsensus DELeteriousness score of missense SNVs), and PON‐P (Pathogenic‐or‐Not–Pipeline) (Sunyaev et al, 2001; Kumar et al, 2009; Schwarz et al, 2010; Gonzalez‐Perez and Lopez‐Bigas, 2011; Olatubosun et al, 2012). Splice‐site prediction of variants was performed with SpliceSiteFinder‐like, MaxEntScan, NNSPLICE, GeneSplicer and Human Splicefinder (Reese et al, 1997; Zhang, 1998; Pertea et al, 2001; Fairbrother et al, 2002; Cartegni et al, 2003; Yeo and Burge, 2004; Desmet et al, 2009; Houdayer et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

GREM1 and POLE variants in hereditary colorectal cancer syndromes

Rohlin

Eiengård

Lundstam

et al. 2015

Genes Chromosomes & Cancer

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Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high‐penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy‐number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease‐causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease‐causing mutations in hereditary CRC syndromes. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

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Improving the Assessment of the Outcome of Nonsynonymous SNVs with a Consensus Deleteriousness Score, Condel

Cited by 719 publications

References 38 publications

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

GREM1 and POLE variants in hereditary colorectal cancer syndromes

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