1. De novo 15q21.1q21.2 deletion identified through FBN1 MLPA and refined by 244K array-CGH in a female teenager with incomplete Marfan syndrome
- Author
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Guillaume Jondeau, Nathalie Ruiz-Pallares, Jean-Damien Metaizeau, Christel Thauvin-Robinet, Frédéric Huet, Francine Mugneret, Fanny Coron, Bruno Leheup, Catherine Boileau, Edith Durand, Patrick Callier, Laurence Faivre, Philippe Khau Van Kien, Aurélie Plancke, Jean-Eric Wolf, Samuel Bidot, Delphine Minot, Corinne Baudoin, Véronique Dulieu, Mireille Claustres, Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de cytogénétique (CHU de Dijon), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Service de Cardiologie [CHU de Dijon], Pôle Rééducation - Réadaptation (Médecine Physique et Réadaptation) (CHU de Dijon), Service orthopédie - traumatologie [CHU de Dijon], Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Ophtalmologie (CHU de Dijon), Centre de référence MARFAN, Hôpital Bichat, Génétique, chromosome et cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de Pédiatrie, and CHU Dijon
- Subjects
Adult ,Male ,musculoskeletal diseases ,Proband ,Marfan syndrome ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,[SDV]Life Sciences [q-bio] ,Fibrillin-1 ,Biology ,Fibrillins ,Bioinformatics ,Polymerase Chain Reaction ,Marfan Syndrome ,Loss of heterozygosity ,03 medical and health sciences ,Transforming Growth Factor beta ,Intellectual Disability ,Genetics ,medicine ,Humans ,Multiplex ligation-dependent probe amplification ,Allele ,Child ,Gene ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Sequence Deletion ,030304 developmental biology ,Chromosomes, Human, Pair 15 ,Comparative Genomic Hybridization ,0303 health sciences ,Microfilament Proteins ,030305 genetics & heredity ,General Medicine ,medicine.disease ,Pedigree ,3. Good health ,Phenotype ,Mutation ,Microsatellite ,Female ,DNA Probes ,Haploinsufficiency ,Microsatellite Repeats - Abstract
International audience; 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.
- Published
- 2010