The FBN1 (R2726W) mutation is not fully penetrant

Buoni, Sabrina; Zannolli, Raffaella; Macucci, Francesca; Ansaldi, Silvia; Grasso, Maurizia; Arbustini, Eloisa; Fois, Alberto

doi:10.1046/j.1529-8817.2004.00113.x

Cited by 21 publications

(18 citation statements)

References 10 publications

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“…It is important to remark that a genetic variant in the FBN1 gene has been previously described in a patient with Marfan syndrome who also suffered epilepsy. However, in this family no other Marfan trait was present [24]. The variant detected in HCN1 gene is a deletion of three amino acids.…”

Section: Discussionmentioning

confidence: 83%

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

et al. 2015

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Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.

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Section: Discussionmentioning

confidence: 83%

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

et al. 2015

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“…The second patient [# 80], was carrier of a known mutation, p.Arg2726Trp, reported as associated with isolated skeletal features of MFS [Milewicz et al, 1995]; he showed skeletal and ocular involvement, absence of cardiovascular signs and of dural ectasia (DE) on lumbo-sacral MRI. He inherited the mutation from the mother who did not show the phenotype [Buoni et al, 2004].…”

Section: Clinical Resultsmentioning

confidence: 99%

“…Only two of our 81 patients were carriers of mutations in C terminus region. Both showed skeletal involvement [Buoni et al, 2004]; one also had aortic root dilation.…”

Section: Discussionmentioning

confidence: 99%

Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies

et al. 2005

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Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue due to mutations of Fibrillin-1 gene (FBN1) in more than 90% of cases and Transforming Growth Factor-Beta-Receptor2 gene (TGFB2R) in a minority of cases. Genotyping is relevant for diagnosis and genotype-phenotype correlations. We describe the FBN1 genotypes and related phenotypes of 81 patients who were referred to our attention for MFS or Marfan-like phenotypes. Patients underwent multidisciplinary pertinent evaluation in the adult or paediatric setting, according to their age. The diagnosis relied on Ghent criteria. To optimise DHPLC analysis of the FBN1 gene, all coding regions of the gene were directly sequenced in 19 cases and 10 controls: heterozygous amplicons were used as true positives. DHPLC sensitivity was 100%. Then, DHPLC was used to screen 62 other cases. We identified 74 FBN1 mutations in 81 patients: 64 were novel and 17 known. Of the 81 mutations, 41 were missense (50.6%), 27, either nonsense or frameshift mutations and predicted a premature termination codon (PTC) (33%), 11 affected splice sites (13.6%), and two predicted in-frame deletions (2.5%). Most mutations (67.9%) occurred in cbEGF-like modules. Genotype was clinically relevant for early diagnosis and conclusion of the diagnostic work-up in patients with incomplete or atypical phenotypes.

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“…Moreover, a single nucleotide substitution in the same codon, causing a preterminal stop codon, was previously described in a Norwegian patient displaying a classic MF phenotype with ectopia lentis, thoracic aorta dilation and systemic features 72 . The other patient showed two mutations, one (Arg2726Trp) was previously associated with variable clinical phenotypes, including mitral valve prolapse (MVP) and myopia 69 , isolated skeletal features 73 , combined skeletal and ocular manifestations 74 , mild skeletal abnormalities 75 ; and a family in which the mutation displayed incomplete penetrance 76 . This mutation was reported in one chromosome of the 1000Genomes and NHLBI Exome Variant Server databases as rs61746008 (http://www.1000genomes.…”

Section: Marfan Syndrome Bav and Fbn1 Mutationsmentioning

confidence: 99%

Bicuspid aortic valve syndrome and fibrillinopathies: potential impact on clinical approach

Pepe¹,

Cario²,

Sticchi³

et al. 2015

ICFJ

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Bicuspid aortic valve (BAV) is a common heterogeneous disorder whose natural history is determined by hemodynamic valvular impairment and/or increased prevalence of aortic abnormalities ranging from dilatation to aneurysm and dissection. BAV-related aortopathy is frequently associated with relevant aortic pathologic changes leading to structural alterations, characteristic degenerative lesions and histological changes of the aorta very similar to those identified and described in patients with Marfan syndrome (MFS), an inherited connective tissue disorder associated with mutations in fibrillin 1 (FBN1) gene in more than 90% of patients. Recently, a 4-fold increase in the prevalence of BAV in MFS patients has been reported. Subsequently, pathogenetic FBN1 mutations in patients with BAV and aortic dilatation/aneurysm in whom MFS and other more severe type 1 fibrillinopathies were clinically excluded have been identified. In this review we discuss how this evidence, together with that of the wide heterogeneity in pathogenetic mechanisms of BAV-related aortopathy, may impact the clinical management of BAV.

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The FBN1 (R2726W) mutation is not fully penetrant

Cited by 21 publications

References 10 publications

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies

Bicuspid aortic valve syndrome and fibrillinopathies: potential impact on clinical approach

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