De novo 15q21.1q21.2 deletion identified through FBN1 MLPA and refined by 244K array-CGH in a female teenager with incomplete Marfan syndrome.
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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ABSTRACT: The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.Clinical Genetics 03/2013; DOI:10.1111/cge.12094 · 3.65 Impact Factor
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ABSTRACT: We report about 52 pediatric patients of 40 different families with confirmed Marfan syndrome (MFS) in 49 patients and Loeys Dietz syndrome (LDS) in 3 patients. We found 39 different mutations, 15 of them being novel. Phenotype-genotype correlation in the 49 MFS patients showed, that the majority of patients carrying mutations in exons 1-21 had ectopic lens (80%). Patients having mutations in exons 23-32 had a higher probability of aortic root dilation, in 50% even above a z-score of 3. We found 3 children with neonatal MFS form, 2 of them with novel mutations. Of the 3 LDS patients, only 1 presented with the typical phenotype of LDS type 1.Clinical Genetics 11/2013; DOI:10.1111/cge.12314 · 3.65 Impact Factor
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ABSTRACT: 2. The history of diagnosing Marfan syndrome 3. The FBN1 gene 4. Overview of literature 5. Different types of FBN1 mutations 6. Conclusion 7. Expert opinion Introduction: Marfan syndrome (MFS) is a connective tissue disorder with highly variable features in cardiovascular, ocular and skeletal systems. MFS is generally caused by one of the 2900-plus described different genetic mutations in the fibrillin-1 gene (FBN1). Areas covered: By revising the Ghent criteria in 2010, more weight has been given to genetic testing in the diagnosis of MFS. We provide an overview of correlations between different mutation types and clinical MFS features by using the Universal Mutation Database (UMD). Expert opinion: In this paper, we classified FBN1 mutations based on their action on DNA level and we found the following genotype--phenotype corre-lations: i) cysteine mutations are associated with ectopia lentis; ii) introduc-tion of a cysteine leads to less severe involvement of cardiovascular and skeletal system; iii) whole gene deletions and premature termination codon (PTC) mutations are associated with increased skeletal and cardiovascular involvement, but lower prevalence of ectopia lentis and iv) intronic mutations lead to MFS by exon skipping, small insertions/deletions and PTC mutations. Classification based on mutation effect at protein level (reduced vs truncated/deformed fibrillin-1) may partly explain genotype--phenotype asso-ciation and warrants further investigation for individualized prognosis and treatment.08/2014; 2(10). DOI:10.1517/21678707.2014.950223