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De novo 15q21.1q21.2 deletion identified through FBN1 MLPA and refined by 244K array-CGH in a female teenager with incomplete Marfan syndrome.

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU Dijon, Université de Bourgogne, Dijon F-21000, France.
European journal of medical genetics (Impact Factor: 1.49). 07/2010; 53(4):208-12. DOI: 10.1016/j.ejmg.2010.05.002
Source: PubMed

ABSTRACT Interstitial deletions involving the 15q21.1 band are very rare. Only 4 of these cases have been studied using molecular cytogenetic techniques in order to confirm the deletion of the whole FBN1 gene. The presence of clinical features of the Marfan syndrome (MFS) spectrum associated with mental retardation has been described in only 2/4 patients. Here we report on a 16-year-old female referred for suspicion of MFS (positive thumb and wrist sign, scoliosis, joint hyperlaxity, high-arched palate with dental crowding, dysmorphism, mitral insufficiency with dystrophic valve, striae). She had therefore 3 minor criteria according to the Ghent nosology. She also had speech disabilities but could follow normal school training. Direct sequencing of the FBN1, TGFBR1 and TGFBR2 genes was negative. MLPA revealed a genomic deletion of the whole FBN1 gene, confirmed by loss of heterozygosity of maternal alleles for several microsatellite markers surrounding the FBN1 gene. The deletion was confirmed by FISH using a FBN1 probe and was not found in the parents. Array-CGH permitted to define a 2.97 Mb deletion, which was the smallest 15q microdeletion including FBN1. Contrary to the other published observations, our proband does not exhibit mental retardation, but neuropsychological evaluations revealed an attention deficit as well as a deficit in information-processing speed. Haploinsufficiency of FBN1 is likely to contribute to the presence of MFS features. However, attenuated features could be explained because disturbances of TGF-beta signalling associated with FBN1 mutations do not exert full phenotypic effect through simple haploinsufficiency. Phenotypic variability in other patients with interstitial deletions including 15q21.1 band may reflect differences in deletion size and/or cys/trans modifying factors.

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    • "The patients described by Adès et al. [8] and Hutchinson et al. [7] had clinical features of the MFS spectrum and mental retardation, but the size of their deletions was not determined. The patient described by Faivre et al. [10] had a 2.97 Mb deletion and some features of MFS but no mental retardation. Hilhorst-Hofstee et al. [2] described 10 cases (five of the same family) with a complete FBN1 gene deletion, screened by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis of 300 patients presenting from mild MFS features to the classical MFS or an MFS-related phenotype. "
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    ABSTRACT: The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature. We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15. This is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.
    Molecular Cytogenetics 01/2012; 5:5. DOI:10.1186/1755-8166-5-5 · 2.66 Impact Factor
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    • "Psychomotor retardation and microcephaly was also described in two of those patients for whom the sizes and breakpoints of their 15 q deletions were unavailable [21,22]. The 16-year-old female described by Faivre et al. [19] harboured a 15q21.1q21.2 micro deletion of 2.97 Mb that encompassed the entire FBN1 and 12 additional genes, including the same genes as the ones involved in patient 2 and 3 of our cohort, although the breakpoints, size and position of the deletions differed between the two studies. "
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    BMC Medical Genetics 09/2011; 12:119. DOI:10.1186/1471-2350-12-119 · 2.45 Impact Factor
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    ABSTRACT: 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.
    European journal of human genetics: EJHG 11/2010; 19(3):247-52. DOI:10.1038/ejhg.2010.174 · 4.23 Impact Factor
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