The perceived impact of the European registration system for genetic counsellors and nurses

The aim of the European Board of Medical Genetics has been to develop and promote academic and professional standards necessary in order to provide competent genetic counselling services. The aim of this study was to explore the impact of the European registration system for genetic nurses and counsellors from the perspectives of those professionals who have registered. Registration system was launched in 2013. A cross-sectional, online survey was used to explore the motivations and experiences of those applying for, and the effect of registration on their career. Fifty-five Genetic Nurses and Counsellors are registered till now, from them, thirty-three agreed to participate on this study. The main motivations for registering were for recognition of their work value and competence (30.3%); due to the absence of a registration system in their own country (15.2%) and the possibility of obtaining a European/international certification (27.3%), while 27.3% of respondents registered to support recognition of the genetic counselling profession. Some participants valued the registration process as an educational activity in its own right, while the majority indicated the greatest impact of the registration process was on their clinical practice. The results confirm that registrants value the opportunity to both confirm their own competence and advance the genetic counselling profession in Europe.</p

Recombinaison entre chromosomes non-disjoints dans la Trisomie 21 et correlations génotypes/phénotypes dans le syndrome de Down

Le syndrome de Down (SD), dont l'origine génétique est majoritairement une trisomie 21, se caractérise par un grand nombre de traits phénotypiques dont la plupart présente une variabilité élevée de sévérité. Une partie de cette variabilité pourrait être due à certaines combinaisons tri-alléliques de polymorphismes nucléotidiques (SNP). Par ailleurs, un événement unique de recombinaison dans la région télomérique des chromosomes 21 homologues augmenterait de 5 fois le risque de non-disjonction. Néanmoins, la distribution fine de ces événements n'est pas connue. Nous avons entrepris d'aborder ces deux types de questions en typant une centaine de SNP du chromosome 21 sur lame de verre chez des patients SD. Nous avons mis au point le typage de deux groupes de cinquante SNP permettant chacun de répondre à l'une des questions énoncées ci-dessus. Le premier groupe couvre 2 mégabases de la région critique du syndrome de Down (21q22.13-q22.2). Nous avons génotypé ces SNP chez 81 patients et étudié les répartitions des génotypes entre patients avec et sans un trait phénotypique donné (dont le retard mental et les cardiopathies). Nous avons observé une association significative après correction de Bonferroni (p<0,001) et une association plus faible (p<0,05) entre deux variants intragéniques du gène KCNJ6 et la présence de cardiopathies congénitales de type anomalie de cloisonnement chez les patients SD. Le rôle potentiel de variants du gène KCNJ6 dans l'apparition d'une cardiopathie constitue une nouvelle piste de travail pour la compréhension de ce phénotype. Le second groupe de SNP étudié couvre les 7,9 Mb télomérique du chromosome 21. Nous n'avons pas observé de différence statistique entre les distributions des recombinaisons associées à une non-disjonction et les contrôles. Néanmoins, la présence d'une recombinaison unique dans une région d'environ 2 Mb, située à 2 Mb du télomère du chromosome 21, semble particulièrement décisive pour l'apparition d'une non-disjonction.Down syndrome (DS), which is mainly caused by trisomy 21, is characterized by many abnormalities affecting most organ systems. The majority of DS features are highly variable between patients in term of presence and severity. Nucleotidic variations (SNPs) within or around some triplicated genes could be partly responsible for this variability. On another hand, fine scale analysis of recombination in the sub-telomeric region should make it more precise the relationship previously reported between altered recombination and meiotic non-disjunction. We addressed these two questions by typing a hundred of SNPs along chromosome 21 in families with a trisomic child. Two set of 50 SNPs have been designed, one for each project. The first 50 SNPs set covers 2 megabases of the Down Syndrome Critical Region (21q22.13-q22.2). We have genotyped 81 patients and studied, for each SNP, the proportion of genotypes between patients with and without a DS trait (including mental retardation and cardiac malformation). We have observed two associations, one strong (p<0,001) and one weaker (p<0,05), between two intragenic SNPs and the presence of a septal cardiac defect. The concerned gene is KCNJ6 a potassium channel which potential implication in DS cardiopathy is a new way of investigations for understanding the variability of this DS trait. The second 50 SNPs set covers the 7.9 sub-telomeric mégabases of chromosome 21. We could not observe significant differences between recombination distributions in context of normal and non-disjoined chromosomes. Nevertheless, the presence of a unique recombination event in a 2 Mb region, located at 2 Mb from the telomere, seems to be critical for the generation of non-disjoined chromosome 21.MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Thirteen years'' experience of 893 PGD cycles for monogenic disorders in a publicly funded, nationally regulated regional hospital service.

International audienceThis study provides an overview of preimplantation genetic diagnosis (PGD) for single gene diseases and the management of expanding indications in the context of a fully financially covered service at Montpellier's regional hospital centre. Within the framework of a restrictive law ruling PGD in France, only the parental genetic risk can be studied in embryos (concurrent aneuploidy screening is not allowed). PCR-based techniques were developed combining mutation detection and closely linked short tandem repeat markers within or flanking the affected genes, and set up more than 100 different robust fluorescent multiplex assays for 61 monogenic disorders. This strategy was used to analyse blastomeres from cleavage-stage embryos. Overall, 893 cycles were initiated in 384 couples; 727 cycles proceeded to oocyte retrieval and 608 cycles to embryo transfer, resulting in 184 deliveries. Clinical pregnancy rate per transfer, implantation and miscarriage rates were 33.6%, 25.1% and 8.8%, respectively. Our PGD programme resulted in the birth of 214 healthy babies for 162 out of 358 couples (45.3%), constituting a relevant achievement within an organizational framework that does not allow aneuploidy screening but provides equal access to PGD, both geographically and socioeconomically. This is a rare example of a fully free-of-charge PGD service

La fabrique du patrimoine écrit

À l’exception d’œuvres de prestige, au premier rang desquelles le public pense aux manuscrits, les objets textuels ne « naissent pas patrimoniaux », ils le deviennent. À partir de plusieurs exemples, littérature de jeunesse, bibliothèque bleue, écrits protestants, presse régionale, etc., les auteurs, universitaires et professionnels des bibliothèques, montrent comment le travail scientifique ou technique conduit à l’affirmation du caractère patrimonial des œuvres, des collections, et même des établissements. Cet ouvrage invite aussi à réfléchir sur le sens des activités professionnelles, pour n’être pas dupe des pratiques lexicales et sociales qui sont au cœur du « patrimoine »

Mosaic complete tetrasomy 21 in a fetus with complete atrioventricular septal defect and minor morphological variations

BACKGROUND: Tetrasomy 21 is a very rare aneuploidy which could clinically resemble a Down syndrome. It was most often described in its partial form than complete. We report the prenatal, pathological and genetic characteristics of a fetus with mosaic complete tetrasomy 21. This is the second well-documented description of a complete tetrasomy 21 in the literature. METHODS: Prenatal and fetal pathological examinations, cytogenetic and molecular analyses were performed to characterize fetal features with tetrasomy 21. RESULTS: Prenatal ultrasound examination revealed an isolated complete atrioventricular septal defect with normal karyotype on amniotic fluid. After termination of pregnancy, clinical examination of the fetus evoked trisomy 21 or Down syndrome. Chromosomal microarray analysis and FISH on lung tissue showed a mosaicism with four copies of chromosome 21 (tetrasomy 21). CONCLUSION: Our observation and the review of the literature reported the possibility of very weak mosaicism and disease-causing confined tissue-specific mosaicism in fetus or alive patients with chromosome 21 aneuploidy, mainly Down syndrome. In case of clinical diagnosis suggestive of Down syndrome, attention must be paid to the risk of false-negative test due to chromosomal mosaicism (very weak percentage, different tissue distribution). To overcome this risk, it is necessary to privilege the diagnostic techniques without culture step and to increase the number of cells and tissues analyzed, if possible. This study highlights the limits of microarray as the unique diagnostic approach in case of weak mosaic and French cytogenetics guidelines recommend to check anomalies seen in microarray by another technique on the same tissue.status: publishe

Mosaic complete tetrasomy 21 in a fetus with complete atrioventricular septal defect and minor morphological variations

International audienceBACKGROUND:Tetrasomy 21 is a very rare aneuploidy which could clinically resemble a Down syndrome. It was most often described in its partial form than complete. We report the prenatal, pathological and genetic characteristics of a fetus with mosaic complete tetrasomy 21. This is the second well-documented description of a complete tetrasomy 21 in the literature.METHODS:Prenatal and fetal pathological examinations, cytogenetic and molecular analyses were performed to characterize fetal features with tetrasomy 21.RESULTS:Prenatal ultrasound examination revealed an isolated complete atrioventricular septal defect with normal karyotype on amniotic fluid. After termination of pregnancy, clinical examination of the fetus evoked trisomy 21 or Down syndrome. Chromosomal microarray analysis and FISH on lung tissue showed a mosaicism with four copies of chromosome 21 (tetrasomy 21).CONCLUSION:Our observation and the review of the literature reported the possibility of very weak mosaicism and disease-causing confined tissue-specific mosaicism in fetus or alive patients with chromosome 21 aneuploidy, mainly Down syndrome. In case of clinical diagnosis suggestive of Down syndrome, attention must be paid to the risk of false-negative test due to chromosomal mosaicism (very weak percentage, different tissue distribution). To overcome this risk, it is necessary to privilege the diagnostic techniques without culture step and to increase the number of cells and tissues analyzed, if possible. This study highlights the limits of microarray as the unique diagnostic approach in case of weak mosaic and French cytogenetics guidelines recommend to check anomalies seen in microarray by another technique on the same tissue

A Broad Test Based on Fluorescent-Multiplex PCR for Noninvasive Prenatal Diagnosis of Cystic Fibrosis

International audienceBACKGROUND:Analysis of cell-free fetal DNA in maternal plasma is very promising for early diagnosis of monogenic diseases. However, it has been limited by the need to set up patient- or disease-specific custom-made approaches. Here we propose a universal test based on fluorescent multiplex PCR and size fragment analysis for an indirect diagnosis of cystic fibrosis (CF).METHODS:The test, based on haplotyping, includes nine intra- and extragenic short tandem repeats of the CFTR locus, the coamplification of p.Phe508del (the most frequent mutation in CF patients worldwide), and a specific SRY sequence. The assay is able to determine the inherited paternal allele.RESULTS:Our simple approach was successfully applied to 30 couples and provided clear results from the maternal plasma. The mean rate of informative markers was sufficient to propose it for use in indirect diagnosis.CONCLUSIONS:This noninvasive prenatal diagnosis test, focused on indirect diagnosis of CF, offers many advantages over current methods: it is simple, rapid, and cost-effective. It allows for the testing of a large number of couples with high risk of CF, whatever the familial mutation of the CFTR gene. It provides an alternative method to reduce the number of invasive tests

Report on three additional patients and genotype–phenotype correlation in SLC25A22-related disorders group

International audienceEarly infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a “suppression burst” (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22 in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype–phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22 that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22 gene

Single Circulating Fetal Trophoblastic Cells Eligible for Non Invasive Prenatal Diagnosis: the Exception Rather than the Rule

International audienceNon-Invasive Prenatal Diagnosis (NIPD), based on the analysis of circulating cell-free fetal DNA (cff-DNA), is successfully implemented for an increasing number of monogenic diseases. However, technical issues related to cff-DNA characteristics remain, and not all mutations can be screened with this method, particularly triplet expansion mutations that frequently concern prenatal diagnosis requests. The objective of this study was to develop an approach to isolate and analyze Circulating Trophoblastic Fetal Cells (CFTCs) for NIPD of monogenic diseases caused by triplet repeat expansion or point mutations. We developed a method for CFTC isolation based on DEPArray sorting and used Huntington’s disease as the clinical model for CFTC-based NIPD. Then, we investigated whether CFTC isolation and Whole Genome Amplification (WGA) could be used for NIPD in couples at risk of transmitting different monogenic diseases. Our data show that the allele drop-out rate was 3-fold higher in CFTCs than in maternal cells processed in the same way. Moreover, we give new insights into CFTCs by compiling data obtained by extensive molecular testing by microsatellite multiplex PCR genotyping and by WGA followed by mini-exome sequencing. CFTCs appear to be often characterized by a random state of genomic degradation