Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder.

Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2, coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T>A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C>G variant encoding the missense p.Pro140Arg in trans with c.1099-1G>A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology.

Psychiatric genetic counseling: A mapping exercise.

Psychiatric genetic counseling (PGC) is gradually developing globally, with countries in various stages of development. In some, PGC is established as a service or as part of research projects while in others, it is just emerging as a concept. In this article, we describe the current global landscape of this genetic counseling specialty and this field's professional development. Drawing on information provided by expert representatives from 16 countries, we highlight the following: (a) current understanding of PGC; (b) availability of services for patients; (c) availability of training; (d) healthcare system disparities and cultural differences impacting practice; and (e) anticipated challenges going forward.

Genetic professionals' views on genetic counsellors: a French survey.

The genetic counselling profession was established in France in 2004. Eight years later, 122 genetic counsellors have graduated from the unique educational French program which awards the Professional Master Degree of Human Pathology, entitled "Master of Genetic Counselling and Predictive Medicine". As part of a global evaluation of this new profession by health genetic professionals, we undertook a national survey investigating various aspects such as employment, work responsibilities and integration. To our knowledge, this is the first study to investigate the views of genetic professionals on the genetic counsellors' role. Of 422 French professionals invited to take part in this study, 126 participated. The survey underlines that this profession is significantly recognized by physicians practicing within genetics departments. French genetic counsellors are allowed to manage consultations independently, without the necessary presence of a qualified medical geneticist but under his or her responsibility. Genetic counsellors participate in a wide range of consultations. They provide both information for relevant and for genetic testing and sometimes disclose the genetic test result to patient. Eventually, the role of genetic counsellors appears to be directly dependent from the relationship of trust between the two health professions.

A Delphi study to determine the European core curriculum for Master programmes in genetic counselling.

Genetic counsellors have been working in some European countries for at least 30 years. Although there are great disparities between the numbers, education, practice and acceptance of these professionals across Europe, it is evident that genetic counsellors and genetic nurses in Europe are working autonomously within teams to deliver patient care. The aim of this study was to use the Delphi research method to develop a core curriculum to guide the educational preparation of these professionals in Europe. The Delphi method enables the researcher to utilise the views and opinions of a group of recognised experts in the field of study; this study consisted of four phases. Phases 1 and 4 consisted of expert workshops, whereas data were collected in phases 2 and 3 (n=35) via online surveys. All participants in the study were considered experts in the field of genetic counselling. The topics considered essential for genetic counsellor training have been organised under the following headings: (1) counselling; (2) psychological issues; (3) medical genetics; (4) human genetics; (5) ethics, law and sociology; (6) professional practice; and (7) education and research. Each topic includes the knowledge, skills and attitudes required to enable genetic counsellors to develop competence. In addition, it was considered by the experts that clinical practice should comprise 50% of the educational programme. The core Master programme curriculum will enable current courses to be assessed and inform the design of future educational programmes for European genetic counsellors.

A study of the practice of individual genetic counsellors and genetic nurses in Europe.

Advances in genetics have meant that the genetic services are now accessed by increasing numbers of patients. One way of dealing with the pressure on services without jeopardising patient care is the inclusion of nonmedical genetic counsellors and genetic nurses in the genetic services team. However, a cohesive approach to the profession has been lacking in Europe, and an educational programme and registration system for European practitioners is required. The aim of this study was to ascertain the type of work undertaken by genetic nurses and counsellors in Europe and the context in which they practised. We used a cross-sectional survey design to collect data from 213 practitioners, either genetic nurses or genetic counsellors, from 18 European countries. Respondents completed the survey online, and data were analysed using descriptive statistics and cross-tabulations. The majority were involved in undertaking the initial contact with the patient (89.9 %) and explaining the genetic test to the patient (91.5 %), while 74 % ordered tests and 91.4 % obtained informed consent for such tests. Psychological support before and after genetic testing was provided by 80.2 % of respondents, and 82.1 % reported regularly managing cases autonomously. While the genetic counselling profession is barely established in some countries, counsellors are able to contribute substantially to patient care as part of the multi-disciplinary team. Further efforts to establish the profession at the European level through a registration process will enhance the confidence in this new group of allied health professionals.

A profile of the genetic counsellor and genetic nurse profession in European countries.

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.

Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial 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.

Using a community of practice to develop standards of practice and education for genetic counsellors in Europe.

The profession of genetic counselling is developing in Europe in response to the increased need for genetic healthcare. Standards of education and professional practice are needed to ensure that patients are provided with genetic counselling of an appropriate quality. However, such standards need to be relevant to practitioners in many different national and healthcare settings. In order to develop appropriate standards and a code of practice to guide professionals in Europe, we formed a community of practice that includes genetic nurses and counsellors, plus other interested health professionals, from 23 European countries. With reference to the European core competences for genetic counsellors, the members of the network developed a set of professional standards for practice, educational standards and a code of practice. It is strongly suggested that the title genetic counsellor should become a protected title in Europe and that practitioners are educated via a master level degree in genetic counselling. These standards have been approved by the members of the network and the existing professional national societies for genetic nurses and counsellors. They provide a foundation for building the profession of genetic counselling in Europe and for provision of equitable care across European countries. Further work is now needed to ensure that appropriate educational opportunities exist to train practitioners and that clinical teams utilise the expertise of these professionals appropriately to enhance the care offered to families at risk of or affected by genetic conditions.

Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.

Approximately 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.

Characterization of six novel mutations in the CYBB gene leading to different sub-types of X-linked chronic granulomatous disease.

Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and so cannot generate superoxide anions (O(2) (-)). The most common form is caused by mutations in CYBB encoding gp91 phox, the heavy chain of flavocytochrome b(558) (XCGD). We investigated 11 male patients and their families suspected of suffering from X-linked CGD. These XCGD patients were classified as having different variants (X91(0), X91(-) or X91(+)) according to their cytochrome b(558) expression and NADPH oxidase activity. Nine patients had X91(0) CGD, one had X91(-) CGD and one had X91(+) CGD. Six mutations in CYBB were novel. Of the four new X91(0) CGD cases, three were point mutations: G65A in exon 2, G387T in exon 5 and G970T in exon 9, leading to premature stop codons at positions Try18, Try125 and Glu320, respectively, in gp91 phox. One case of X91(0) CGD originated from a new 1005G deletion detected in exon 9. Surprisingly, four nonsense mutations in exon 5 led to the generation of two mRNAs, one with a normal size containing the mutation and the other in which exon 5 had been spliced. A novel X91(-) CGD case with low gp91 phox expression was diagnosed. It was caused by an 11-bp deletion in the linking region between exon 12 and intron 12, activating a new cryptic site. Finally, a new X91(+) CGD case was detected, characterized by a missense mutation Leu505Arg in the potential NADPH-binding site of gp91 phox. No clear correlation between the severity of the clinical symptoms and the sub-type of XCGD could be established.

Allelic variations at the haploid TBX1 locus do not influence the cardiac phenotype in cases of 22q11 microdeletion.

Microdeletion at the 22q11 locus is characterised by a high clinical variability. Congenital heart defects (CHD) are the most life-threatening manifestations of the syndrome and affect approximately 50% of patients carrying the deleted chromosome 22. The causes of this phenotype variability remain unknown although several hypotheses have been raised. It has been suggested that allelic variations at the haploid locus could modify the phenotypic expression. Regarding this hypothesis, TBX1 was thought to be a major candidate to the cardiac phenotype or its severity in patients carrying the 22q11 microdeletion. A mutational screening was performed in this gene, in a series of 39 deleted patients, with and without CHD. The results indicate that mutations in TBX1 are not likely to be involved in the cardiac phenotype observed in del22q11 patients.