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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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| 2. |
- 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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| 6. |
- Koido, Kati, et al.
(författare)
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Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe : A multi-professional survey study
- 2023
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Ingår i: European Journal of Medical Genetics. - : Elsevier. - 1769-7212 .- 1878-0849. ; 66:8
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Tidskriftsartikel (refereegranskat)abstract
- Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field.We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders.Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant.We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe.
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| 8. |
- Sorensen, Karina Meden, et al.
(författare)
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Screening of Congenital Heart Disease Patients Using Multiplex Ligation-Dependent Probe Amplification: Early Diagnosis of Syndromic Patients
- 2012
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825. ; 158A:4, s. 720-725
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Tidskriftsartikel (refereegranskat)abstract
- Recurrent copy number variants (CNVs) are found in a significant proportion of patients with congenital heart disease (CHD) and some of these CNVs are associated with other developmental defects. In some syndromic patients, CHD may be the first presenting symptom, thus screening of patients with CHD for CNVs in specific genomic regions may lead to early diagnosis and awareness of extracardiac symptoms. We designed a multiplex ligation-dependent probe amplification (MLPA) assay specifically for screening of CHD patients. The MLPA assay allows for simultaneous analysis of CNVs in 25 genomic regions previously associated with CHD. We screened blood samples from 402 CHD patients and identified 14 rare CNVs in 13 (3.2%) patients. Five CNVs were de novo and six where inherited from a healthy parent. The MLPA screen led to early syndrome diagnosis in two of these patients. We conclude that the MLPA assay detects clinically relevant CNVs and suggest that it could be used within pediatric cardiology as a first tier screen to detect clinically relevant CNVs and identify syndromic patients at an early stage. (C) 2012 Wiley Periodicals, Inc.
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| 9. |
- Davidsson, Josef, et al.
(författare)
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dup(19)(q12q13.2): Array-based Genotype-Phenotype Correlation of a New Possibly Obesity-related Syndrome.
- 2010
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Ingår i: Obesity. - : Wiley. - 1930-739X .- 1930-7381. ; 18, s. 580-587
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Tidskriftsartikel (refereegranskat)abstract
- Small supernumerary marker chromosomes (sSMCs) derived from the near-centromeric area of chromosome 2 are very rare. In addition, duplications of the 2p11.2-->q11.2 region have displayed considerable variability between patients harboring and lacking clinical findings. Moreover, constitutional duplication of the 19q12-->q13.2 region has previously only been described in two cases and was associated with delay of developmental milestones, corpus callosum anomalies, and obesity. Herein, we present a genotype-phenotype correlation in a patient harboring two sSMCs derived from chromosomes 2 and 14 or 22, respectively. The DNA was studied using G-banding, fluorescence in situ hybridization techniques, and array-based comparative genomic hybridization. A 48,XX,+der(2)del(2)(p11)del(2)(q11.2),+der(14)t(14;19)(q11;q12)del(19)(q13.31) or 48,XX,+der(2)del(2)(p11)del(2)(q11.2),+der(22)t(22;19)(q11;q12)del(19)(q13.31) was detected in the patient. The sSMC 14;19 or 22;19, with its centromere originating from either chromosome 14 or 22, encompassed a 13.56 megabase (Mb) 19q derived region, harboring 263 genes, and the sSMC 2 a 2.71 Mb region including 29 genes. The patient had symptoms including a ventral septal defect, bilateral grade IV urinary reflux, corpus callosum agenesis, microphthalmia, and obesity. The 19q segment contained the genes AKT2, CEACAM1, CEBPA, LIPE, and TGFB1 which are involved in adipose tissue homeostasis and insulin resistance, and could potentially contribute to the obese phenotype observed. Array-based genetic characterization and long-term clinical evaluation with attention toward weight gain in patients with chromosome 19q duplications might in the future lead to the description of a obesity-associated genetic syndrome, something that could have implications in management and treatment of patients carrying a dup(19)(q12q13.2). Whether the der(2)(p11q11.2) contributes to the phenotype remains inconclusive.
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| 10. |
- Gudjonsson, Sigurdur, et al.
(författare)
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The Value of the UroVysion((R)) Assay for Surveillance of Non-Muscle-Invasive Bladder Cancer.
- 2008
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 54:2, s. 402-408
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Patients with non-muscle-invasive bladder cancer are traditionally followed by repeat cystoscopy and urine cytology. A fluorescence in situ hybridisation technique called UroVysion((R)) (UV) is now available for clinical diagnosis of urothelial cancer cells. The aim of the present study was to compare UV analysis with routine follow-up methods. METHODS: We studied an unselected cohort of patients undergoing cystoscopy follow-ups at two Swedish centres in 2004-2005. All patients were investigated by cystoscopy, cytology, and UV assay. The UV assay was evaluated with regards to sensitivity, specificity, and positive predictive value for tumour recurrence. RESULTS: In all, 159 cases were analysed. UV had a 30% overall sensitivity for the 27 biopsy-proven recurrences and 70% sensitivity for high-risk tumours (pT1 and carcinoma in situ [CIS]). The specificity of UV was 95%. UV detected all six CIS cases in the study and was predictive in two additional patients who developed CIS within 1 yr of inclusion. Cytology was positive in four of those eight CIS cases and atypical in the other four. CONCLUSIONS: The UV assay cannot replace cystoscopy for surveillance of patients with non-muscle-invasive bladder cancer, but it may be valuable as a supplement to traditional measures for detecting CIS. Before any conclusions can be drawn regarding the efficacy of novel markers of bladder cancer, they must be studied in bladder cancer patients undergoing endoscopic surveillance.
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