Confirmation of a founder effect in a Northern European population of a new ß-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA)).

ß-Thalassemia is a genetic disease caused by a defect in the production of the ß-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of four nucleotides in the first exon of ß-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the ß-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (nine generations). In order to determine whether this variant arose in this region of Northern Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare ß-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe.

Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level.

With the increased number of identified nucleotide sequence variations in genes, the current challenge is to classify them as disease causing or neutral. These variants of unknown clinical significance can alter multiple processes, from gene transcription to RNA splicing or protein function. Using an approach combining several in silico tools, we identified some exons presenting weaker splicing motifs than other exons in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. These exons exhibit higher rates of basal skipping than exons harboring no identifiable weak splicing signals using minigene assays. We then screened 19 described mutations in three different exons, and identified exon-skipping substitutions. These substitutions induced higher skipping levels in exons having one or more weak splicing motifs. Indeed, this level remained under 2% for exons with strong splicing motifs and could reach 40% for exons having at least one weak motif. Further analysis revealed a functional exon splicing enhancer within exon 3 that was associated with the SR protein SF2/ASF and whose disruption induced exon skipping. Exon skipping was confirmed in vivo in two nasal epithelial cell brushing samples. Our approach, which point out exons with some splicing signals weaknesses, will help spot splicing mutations of clinical relevance.

From MIP image to MRA segmentation using fuzzy set theory.

The aim of this paper is to describe a semi-automatic method of segmentation in magnetic resonance angiography (MRA). This method, based on fuzzy set theory, uses the information (gray levels) contained in the maximum intensity projection (MIP) image to segment the 3D vascular structure from slices. Tests have been carried out on vascular phantom and on clinical MRA images. This 3D segmentation method has proved to be satisfactory for the detection of vascular structures even for very complex shapes. Finally, this MIP-based approach is semi-automatic and produces a robust segmentation thanks to the contrast-to-noise ratio and to the slice profile which are taken into account to determine the membership of a voxel to the vascular structure.

A global approach for automatic artifact removal for standard EEG record.

The EEG signal is a record of the brain activity using multiple electrodes placed on the scalp. Unfortunately, it can be hardly contaminated by a lot of noises called artifacts. These latter can be generated by various actions such as eye blinks, eye movements or the skeletal muscle activities (jaw, forehead, ...). This study will focus on a global artifact removal method using independent component analysis (ICA) on signals cut in frequency bands. The interest of this method resides in automatizing the artifactual source identification and enables a global filtering of records using constant bases. A brief overview of the project will be made in order to introduce the method used. Next, the results will be presented and their validation will be discussed in the conclusion.

Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver-Russell patient.

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver-Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well-recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved.