Communicated by Haig H. KazazianApproximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single-and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients. Hum Mutat 28(2), [196][197][198][199][200][201][202] 2007.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the absence of a maternal contribution to chromosome 15q11-q13. There are four classes of AS according to molecular or cytogenetic status: maternal microdeletion of 15q11-q13 (approximately 70% of AS patients); uniparental disomy (UPD); defects in a putative imprinting centre (IM); the fourth includes 20-30% of AS individuals with biparental inheritance and a normal pattern of allelic methylation in 15q11-q13. Mutations of UBE3A have recently been identified as causing AS in the latter group. Few studies have investigated the phenotypic differences between these classes. We compared 20 non-deletion to 20 age-matched deletion patients and found significant phenotypic differences between the two groups. The more severe phenotype in the deletion group may suggest a contiguous gene syndrome.

Previously, we localized the defective gene for the urofacial syndrome (UFS) to a region on chromosome 10q24 by homozygosity mapping. We now report evidence that Heparanse 2 (HPSE2) is the culprit gene for the syndrome. Mutations with a loss of function in the Heparanase 2 (HPSE2) gene were identified in all UFS patients originating from Colombia, the United States, and France. HPSE2 encodes a 592 aa protein that contains a domain showing sequence homology to the glycosyl hydrolase motif in the heparanase (HPSE) gene, but its exact biological function has not yet been characterized. Complete loss of HPSE2 function in UFS patients suggests that HPSE2 may be important for the synergic action of muscles implicated in facial expression and urine voiding.

Quality genetic healthcare services should be available throughout Europe. However, due to enhanced diagnostic and genetic testing options, the pressure on genetic counselling services has increased. It has been shown in many countries that appropriately trained genetic counsellors and genetic nurses can offer clinical care for patients seeking information or testing for a wide range of genetic conditions. The European Society of Human Genetics is setting up a system of accreditation for genetic counsellors, to ensure safe practice, however there has been little information about the practice and education of non-medical genetic counsellors in Europe. To collect baseline data, we approached key informants (leaders in national genetics organisations or experienced practitioners) to complete an online survey, reporting on the situation in their own country. Twenty-nine practitioners responded, providing data from 18 countries. The findings indicate huge variation in genetic counsellor numbers, roles, and education across Europe. For example, in UK and The Netherlands, there are more than four counsellors per million population, while in Germany, Hungary, Turkey, and Czech Republic, there are no non-medical counsellors. There are specific educational programmes for genetic counsellors in seven countries, but only France has a specific governing legal framework for genetic counsellors. In the post-genomic era, with added pressure on health systems due to increases in availability and use of genetic testing, these disparities are likely to result in inequalities in service provided to European citizens. This study underpins the need for a coherent European approach to accreditation of genetic counsellors.