<i>FBN1</i>, <i>TGFBR1</i>, and the Marfan‐craniosynostosis/mental retardation disorders revisited

Adès, Lesley C.; Sullivan, Kathleen E.; Biggin, Andrew; Haan, Eric; Brett, Maggie; Holman, Katherine; Dixon, Joanne; Robertson, Stephen; Holmes, Anthony D.; Rogers, John G.; Bennetts, Bruce

doi:10.1002/ajmg.a.31202

Cited by 82 publications

(65 citation statements)

References 28 publications

(43 reference statements)

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“…However, in most of these reports, the deletion of FBN1 or the presence of marfanoid features are not discussed [24][25][26][27][28][29] . In four reports, the deletion of FBN1 is confirmed by molecular techniques, with marfanoid features in three cases 18,19,21 and absence of marfanoid features in one case, which could be due to the young age of this patient. 20 In this study, we describe 10 patients with a deletion of an entire FBN1 allele.…”

Section: Discussionmentioning

confidence: 82%

“…[12][13][14][15][16][17] Only four reports are known of a molecularly proven whole-gene deletion of FBN1. [18][19][20][21] We describe 10 patients, including a family with five patients with whole-gene deletions, and show that complete loss of one FBN1 allele does not predict a mild phenotype. These findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.…”

Section: Introductionmentioning

confidence: 97%

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The clinical spectrum of complete FBN1 allele deletions

et al. 2010

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The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 97%

The clinical spectrum of complete FBN1 allele deletions

et al. 2010

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“…1) (Ades et al 2006). One of these patients had learning difficulties, and the other had normal intelligence (Ades et al 2006).…”

Section: Shprintzen-goldberg Craniosynostosis Syndromementioning

confidence: 95%

“…1) (Ades et al 2006). One of these patients had learning difficulties, and the other had normal intelligence (Ades et al 2006). Systemic arterial tortuosity was not evaluated in either of them, but one showed bifid uvula, consistent with LDS.…”

Section: Shprintzen-goldberg Craniosynostosis Syndromementioning

confidence: 97%

“…At least six TGFBR2 mutations (R356P, N384S, R460H, R460C, S449F, and R537C) and two TGFBR1 mutations (S241L and R487Q) were recognized in two or three conditions (i.e., R460H found in MFS, LDS, and TAAD) (Ades et al 2006;Disabella et al 2006;Ki et al 2005;Loeys et al 2006;Matyas et al 2006;Mizuguchi et al 2004;Pannu et al 2005a;Sakai et al 2006;Singh et al 2006) (Fig. 1, Table 2), implying that TGFBR mutations may cause various clinical consequences or that appropriate diagnosis is rather difficult for these disorders.…”

Section: Germline Tgfbr Mutations and Connective Tissue Disordersmentioning

confidence: 99%

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Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

2006

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Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFb) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including LoeysDietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFb signaling plays a significant role in these disorders.

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Molecular Genetics of Aortic Aneurysms and Aortic Dissections

Regalado

Milewicz

2015

Encyclopedia of Life Sciences

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A genetic predisposition to aortic aneurysms and dissections can occur as part of a genetic syndrome, such as Marfan and Loeys‐Dietz syndrome, or as an isolated manifestation without other systemic features, referred to as familial thoracic aortic aneurysms and dissections. These genetic disorders are inherited as autosomal dominant conditions with reduced penetrance and variable expressivity in terms of aortic disease presentation, age of onset and extent of cardiovascular and other systemic involvement. Mutations in the FBN1 , TGFBR1 , TGFBR2 , SMAD3 , SMAD4 , TGFB2 , ACTA2 , MYH11 , MYLK and PRKG1 have been identified in patients with syndromic and non‐syndromic TAAD, emphasising the important roles of the transcription growth factor beta signalling pathway and smooth muscle contraction in aortic disease development. Key Concepts Thoracic aortic aneurysms and dissections or TAAD can occur as part of a genetic syndrome, such as Marfan syndrome, Loeys‐Dietz syndrome or as an isolated manifestation without syndromic features. Approximately 20% of patients with TAAD who do not have Marfan syndrome or related disorder have a similarly affected relative, referred to as familial thoracic aortic aneurysm and dissection or FTAAD. Marfan syndrome, Loeys‐Dietz syndrome and FTAAD are primarily inherited in an autosomal dominant pattern with reduced penetrance and variable expressivity. FTAAD is a genetically and clinically heterogeneous group of disorders caused by mutations in several genes, including FBN1 , TGFBR1 , TGFBR2 , SMAD3 , SMAD4 , TGFB2 , ACTA2 , MYH11 , MYLK and PRKG1 .

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FBN1, TGFBR1, and the Marfan‐craniosynostosis/mental retardation disorders revisited

Cited by 82 publications

References 28 publications

The clinical spectrum of complete FBN1 allele deletions

The clinical spectrum of complete FBN1 allele deletions

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

Molecular Genetics of Aortic Aneurysms and Aortic Dissections

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