TGGE screening of the entire FBN1 coding sequence in 126 individuals with Marfan syndrome and related fibrillinopathies and mutation analysis in view of genotype-phenotype correlations

Mutationen im Fibrillin-1 Gen (FBN1) führen zum Marfan-Syndrom (MFS), einer autosomal dominanten Erkrankung des Bindegewebes mit Manifestationen im skelettalen, okulären und kardiovaskulären System. FBN1 Mutationen wurden zudem bei einer Reihe weiterer Erkrankungen des Bindegewebes gefunden, die man als Typ-1 Fibrillinopathie bezeichnet. Es wurden Temperatur-Gradienten-Gel Elektrophorese (TGGE) Assays für die kodierenden Exone 1-58 des FBN1 entwickelt, um 126 Patienten mit MFS und verwandten Fibrillinopathien zu untersuchen. Es wurden insgesamt 45 Mutationen gefunden, von denen 41 erstmals beschrieben werden konnten. Einige Mutationen wurden bei Individuen mit Typ-1-Fibrillinopathien gefunden, die nicht die Diagnosekriterien des „klassischen“ MFS erfüllten. Auf der Grundlage der gefundenen Mutationen, im Vergleich zu bereits veröffentlichten Mutationen in der Literatur erfolgte die Analyse in Bezug auf mögliche Genotyp-Phänotyp-Korrelationen. In der Mitte des Gens, in den Exonen 24-32, zeigte sich vor allem für das neonatale MFS (nMFS), einer besonders schwerwiegenden Variante der Erkrankung, die oft schon innerhalb der ersten 12 Monate tödlich verläuft, eine klare Häufung an Mutationen. Mutationen im Bereich der 5`-Region zeigten in der Mehrzahl der Fälle milde Phänotypen mit dem Fehlen kardiovaskulärer Symptome oder allenfalls mit einer sehr milden kardiovaskulären Beteiligung. Die Mutationsdetektionsrate der gesamten Studie betrug 42%. In der Gruppe der Patienten mit „klassischem“ MFS lag sie bei 51%. Patienten, die die Kriterien der Genter Nosologie nicht erfüllten, zeigten eine Mutationsdetektionsrate von nur 12%. Ursächlich scheint hier v.a. eine klinische Überdiagnostik zu einer verminderten Mutationsdetektionsrate zu führen.Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome (MFS), an autosomal dominant heritable disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. FBN1 mutations have also been identified in a series of related disorders of connective tissue collectively termed type-1 fibrillinopathies. We have developed temperature-gradient gel electrophoresis (TGGE) assays for FBN1 exons 1-58, screened 126 individuals with MFS, other type-1 fibrillinopathies, and other potentially related disorders of connective tissue for FBN1 mutations, and identified a total of 45 mutations, of which 41 are described here for the first time. Several mutations were identified in individuals with fibrillinopathies other than classic Marfan syndrome. We compared the identified mutations with mutations previously reported in the literature to assay putative genotype-phenotype correlations. An association with a subset of mutations in exons 24-32 and neonatal MFS, the severest end of the clinical spectrum which leads to death within the first month of live was found. Mutations located in the 5`-region were associated with relatively mild involvement. The mutation detection rate in this study was 42% overall, but was only 12% in individuals not fulfilling the diagnostic criteria for MFS, suggesting that clinical overdiagnosis is one reason for the low detection rate observed for FBN1 mutation analysis

Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies

The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a series of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS, and at least 337 mainly unique mutations have been published to date. FBN1 mutations have been found not only in MFS but also in a range of connective tissue disorders collectively termed fibrillinopathies ranging from mild phenotypes, such as isolated ectopia lentis, to severe disorders including neonatal MFS, which generally leads to death within the first two years of life. The present article intends to provide an overview of mutations found in MFS and related disorders and to discuss potential genotype-phenotype correlations in MFS

TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome (MFS), an autosomal dominant heritable disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. FBN1 mutations have also been identified in a series of related disorders of connective tissue collectively termed type-1 fibrillinopathies. We have developed temperature-gradient gel electrophoresis (TGGE) assays for all 65 FBN1 exons, screened 126 individuals with MFS, other type-1 fibrillinopathies, and other potentially related disorders of connective tissue for FBN1 mutations, and identified a total of 53 mutations, of which 33 are described here for the first time. Several mutations were identified in individuals with fibrillinopathies other than classic Marfan syndrome, including aneurysm of the ascending aorta with only minor skeletal anomalies, and several individuals with only skeletal and ocular involvement. The mutation detection rate in this study was 42% overall, but was only 12% in individuals not fulfilling the diagnostic criteria for MFS, suggesting that clinical overdiagnosis is one reason for the low detection rate observed for FBN1 mutation analysis. Hum Mutat 20:197-208, 2002. © 2002 Wiley-Liss, Inc

Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer

Background: CA125 is the best available yet insufficiently sensitive biomarker for early detection of ovarian cancer. There is a need to identify novel biomarkers, which individually or in combination with CA125 can achieve adequate sensitivity and specificity for the detection of earlier-stage ovarian cancer. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we measured serum levels of 92 preselected proteins for 91 women who had blood sampled ≤18 months prior to ovarian cancer diagnosis, and 182 matched controls. We evaluated the discriminatory performance of the proteins as potential early diagnostic biomarkers of ovarian cancer. Results: Nine of the 92 markers; CA125, HE4, FOLR1, KLK11, WISP1, MDK, CXCL13, MSLN and ADAM8 showed an area under the ROC curve (AUC) of ≥0.70 for discriminating between women diagnosed with ovarian cancer and women who remained cancer-free. All, except ADAM8, had shown at least equal discrimination in previous case-control comparisons. The discrimination of the biomarkers, however, was low for the lag-time of >9–18 months and paired combinations of CA125 with any of the 8 markers did not improve discrimination compared to CA125 alone. Conclusion: Using pre-diagnostic serum samples, this study identified markers with good discrimination for the lag-time of 0–9 months. However, the discrimination was low in blood samples collected more than 9 months prior to diagnosis, and none of the markers showed major improvement in discrimination when added to CA125