9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping.

The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.

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

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.