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- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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- Nilsson, D., et al.
(författare)
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From cytogenetics to cytogenomics : whole genome sequencing as a comprehensive genetic test in rare disease diagnostics
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 27, s. 1666-1667
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Rare genetic diseases are caused by different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements. Recent data indicates that whole genome sequencing (WGS) may be used as a comprehensive test to identify multiple types of pathologic genetic aberrations in a single analysis.We present FindSV, a bioinformatic pipeline for detection of balanced (inversions and translocations) and unbalanced (deletions and duplications) structural variants (SVs). First, FindSV was tested on 106 validated deletions and duplications with a median size of 850 kb (min: 511 bp, max: 155 Mb). All variants were detected. Second, we demonstrated the clinical utility in 138 monogenic WGS panels. SV analysis yielded 11 diagnostic findings (8%). Remarkably, a complex structural rearrangement involving two clustered deletions disrupting SCN1A, SCN2A, and SCN3A was identified in a three months old girl with epileptic encephalopathy. Finally, 100 consecutive samples referred for clinical microarray were also analyzed by WGS. The WGS data was screened for large (>2 kbp) SVs genome wide, processed for visualization in our clinical routine arrayCGH workflow with the newly developed tool vcf2cytosure, and for exonic SVs and SNVs in a panel of 700 genes linked to intellectual disability. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. The diagnostic rate (29%) was doubled compared to clinical microarray (12%).In conclusion, using WGS we have detected a wide range of structural variation with high accuracy, confirming it a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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- Johnston, Jennifer J., et al.
(författare)
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Molecular Analysis Expands the Spectrum of Phenotypes Associated with GLI3 Mutations
- 2010
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 31:10, s. 1142-1154
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Tidskriftsartikel (refereegranskat)abstract
- A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial- digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria. Hum Mutat 31:1142-1154, 2010. (C) 2010 Wiley-Liss, Inc.
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- Rodriguez-Palmero, Agusti, et al.
(författare)
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DLG4-related synaptopathy : a new rare brain disorder
- 2021
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 23:5, s. 888-899
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Tidskriftsartikel (refereegranskat)abstract
- PurposePostsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.MethodsThe clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.ResultsThe clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.ConclusionThe present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
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- Valind, Anders, et al.
(författare)
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The fetal thymus has a unique genomic copy number profile resulting from physiological T cell receptor gene rearrangement
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mosaicism, the presence of genetically distinct cells within an organism, has been increasingly associated with human morbidity, ranging from being a cause of rare syndromes to a risk factor for common disorders such as malignancy and cardiovascular disease. Previous studies interrogating the normal prevalence of somatic mosaicism have focused on adults. We here present an estimate of the baseline frequency of somatic mosaic copy number variation (CNV) at the time around birth, by sampling eight different organs from a total of five fetuses and newborns. Overall we find a significantly lower frequency of organ specific (i.e. mosaic) CNVs as compared to adults (p = 0.003; Mann-Whitney U-test). The rate of somatic CNV in adults has been estimated to around 2.2 CNV per organ assayed. In contrast, after stringent filtering, we found no organ-private CNVs in fetuses or newborns with exception of the thymus. This organ exhibited a specific genome profile in the form of deletions resulting from polyclonal T-cell receptor rearrangements. This implies that somatic non-immune related CNVs, if present at birth, are typically confined to very small cell populations within organs.
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- Lombardi, Maria Paola, et al.
(författare)
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Mutation update for the PORCN gene
- 2011
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Ingår i: Human Mutation. - : Wiley-Blackwell. - 1059-7794 .- 1098-1004. ; 32:7, s. 723-728
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software, and is accessible online at http://www.lovd.nl/porcn. At present, the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients.
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- Ygland, E., et al.
(författare)
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Friedreich's ataxia in patients with FXN p.R165P point mutation
- 2012
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 19:Suppl 1, s. 727-727
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Konferensbidrag (refereegranskat)abstract
- Introduction: Friedreich's ataxia (FRDA) is a hereditary disorder with progressive postural ataxia, dysarthria, neuropathy, muscle weakness and cardiomyopathy. Lack or malfunction of the protein frataxin due to mutations in the frataxin gene (FXN) is the cause of the disease. Most patients are homozygous for GAA trinucleotide expansions in FXN but disease can also be caused by heterozygosity for the expansion and a point mutation. Milder disease has been reported for some FRDA patients with missense mutations. Methods: We describe 3 FRDA patients, not previously reported, with the FXN p.R165P missense mutation and compared clinical features with 6 homozygous GAA expansion carriers. Patients were interviewed, examined clinically and assessed with FRDA rating scale (FARS). Blood was collected for reanalysis of GAA expansion length and for frataxin measurements. Results: Compared to patients homozygous for FXN GAA expansion, p.R165P mutation carriers had more wellpreserved upper limb function and deep tendon reflexes, considerably milder dysarthria, but possibly an increased occurrence of psychosis. p.R165P patients were more independent in activities of daily living, especially when correlated to disease duration. We found no difference in other clinical aspects or in GAA expansion length. One patient had severe FRDA symptoms and comorbid hemochromatosis, whereas his sibling without hemochromatosis had much milder disease. Refined analysis of GAA expansion length and frataxin levels are in progress. Conclusion: p.R165P FRDA patients appear to progress to a less disabling disease state than typical FRDA. We suggest additive effects of comorbid FRDA and hemochromatosis, due to synergistic abnormalities in iron metabolism.
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- Buchanan, James, et al.
(författare)
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Factor's that impact on women's decision-making around prenatal genomic tests : An international discrete choice survey
- 2022
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Ingår i: Prenatal Diagnosis. - : John Wiley & Sons. - 0197-3851 .- 1097-0223. ; 42:7, s. 934-946
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Tidskriftsartikel (refereegranskat)abstract
- Objective We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. Methods Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. Results Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. Conclusion Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.
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