Multi-exon out of frame deletion of the FBN1 gene leading to a severe juvenile onset cardiovascular phenotype in Marfan syndrome

Singh, Krishna K.; Elligsen, Diana; Liersch, Rüdiger; Schubert, Stefanie; Pabst, Brigitte; Arslan‐Kirchner, Mine; Schmidtke, Jörg

doi:10.1016/j.yjmcc.2006.11.006

Cited by 18 publications

(13 citation statements)

References 17 publications

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“…Various types of mutations (e.g., cysteine, whole exon, PTC) have been reported to predict phenotype; whole exon deletions have previously been associated with a severe phenotype [Liu et al, 2001; Singh et al, 2007]. There was support for this observation from two patients included in this study with whole exon deletions, both of whom presented with MFS features in early childhood.…”

Section: Discussionsupporting

confidence: 62%

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Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype–phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy

Turner

Emery

Collins

et al. 2009

American J of Med Genetics Pt A

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Mutations in the gene encoding fibrillin 1 (FBN1) cause Marfan syndrome (MFS), and related connective tissue disorders. The disease spectrum is wide and while many genotype-phenotype correlations have been reported, few have been consistent. In this study FBN1 was analyzed in 113 patients with MFS or Marfan-like features. Fifty-three mutations were identified in 52 individuals, 41 of which were novel. The mutations comprised 26 missense, 11 splice site, 7 frameshift, 6 nonsense, 1 in-frame deletion, and 2 whole exon deletions. In common with previous studies, genotype-phenotype analysis showed that a FBN1 mutation was more likely to be identified in patients fulfilling Ghent criteria (P = 0.005) and in those who had ectopia lentis (EL) (P < 0.0001). Other previously reported genotype-phenotype correlations were also considered and a new inverse association between a mutation in exons 59-65, and EL emerged (P = 0.002).

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Section: Discussionsupporting

confidence: 62%

“…Multi‐exon deletions have been reported to cause “severe” early onset disease [Liu et al, 2001; Singh et al, 2007]. In this study, there were two patients with whole exon deletions described in detail previously [Blyth et al, 2008].…”

Section: Resultsmentioning

confidence: 69%

Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype–phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy

Turner

Emery

Collins

et al. 2009

American J of Med Genetics Pt A

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“…See also Figs. 2 and 3 e The nucleotide at position +325 in intron 41 is joined to the nucleotide in position +314 in intron 43 (Liu et al 2001) f The breakage and rejoining occurred within the pentamer (atttt) at positions ¡282 to ¡278 of intron 43 and positions ¡325 to ¡321 of intron 46 (Liu et al 2001) g In the study of Loeys et al (2004), this deletion involving exon 52 was not identiWed by mutation screening of FBN1 genomic DNA but by cDNA analyses and was described solely at the protein level as presented here h This deletion was originally published by Kainulainen et al (1992) as c.4,762_5,127del366 using an at that time incomplete FBN1 cDNA sequence for the description i The nucleotide at position ¡88 in intron 57 is joined to the nucleotide in position +1,062 in intron 63 (Singh et al 2007 Singh et al (2007) …”

Section: T T T T Gaa Ta T T Ttca G Tac T T Taa Aca Gc C Tac Ccc a T Amentioning

confidence: 99%

Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome

et al. 2007

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Mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, which displays variable manifestations in the cardiovascular, ocular, and skeletal systems. Current molecular genetic testing of FBN1 may miss mutations in the promoter region or in other noncoding sequences as well as partial or complete gene deletions and duplications. In this study, we tested for copy number variations by successively applying multiplex ligation-dependent probe amplification (MLPA) and the Affymetrix Human Mapping 500 K Array Set, which contains probes for approximately 500,000 single-nucleotide polymorphisms (SNPs) across the genome. By analyzing genomic DNA of 101 unrelated individuals with MFS or related phenotypes in whom standard genetic testing detected no mutation, we identified FBN1 deletions in two patients with MFS. Our high-resolution approach narrowed down the deletion breakpoints. Subsequent sequencing of the junctional fragments revealed the deletion sizes of 26,887 and 302,580 bp, respectively. Surprisingly, both deletions affect the putative regulatory and promoter region of the FBN1 gene, strongly indicating that they abolish transcription of the deleted allele. This expectation of complete loss of function of one allele, i.e. true haploinsufficiency, was confirmed by transcript analyses. Our findings not only emphasize the importance of screening for large genomic rearrangements in comprehensive genetic testing of FBN1 but, importantly, also extend the molecular etiology of MFS by providing hitherto unreported evidence that true haploinsufficiency is sufficient to cause MFS.

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“…Most of these deletions are associated with a severe or classical Marfan phenotype. [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.…”

Section: Introductionmentioning

confidence: 99%

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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Multi-exon out of frame deletion of the FBN1 gene leading to a severe juvenile onset cardiovascular phenotype in Marfan syndrome

Cited by 18 publications

References 17 publications

Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype–phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy

Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype–phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy

Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome

The clinical spectrum of complete FBN1 allele deletions

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