ABSTRACT
The treatment of spinal muscular atrophy (SMA) has considerably changed over the last 3 years. Several approaches that aim to increase the deficient SMN protein have demonstrated an efficacy that is inversely correlated with disease duration. In this context, newborn screening (NBS) is increasingly considered as the next step in several countries or regions. In 2018, we initiated a pilot study for NBS of SMA in French- and German-speaking Belgium. We aim to evaluate the feasibility, the efficacy, and the cost-effectiveness of such a program. Initially covering the region of Liege, the program was recently extended to the whole Southern Belgium and currently covers about 55.000 newborns per year. On June 1st 2019, 35.000 newborns had been screened and 5 affected babies were identified and referred to neuromuscular centers for early treatment. A full evaluation of the program will take place after three years to consider the inclusion of SMA screening in the publically-funded NBS program in Southern Belgium.
La prise en charge de l'amyotrophie spinale antérieure (SMA) a considérablement évolué au cours des trois dernières années. Les différents essais visant à augmenter la production de la protéine SMN déficitaire dans la SMA ont systématiquement montré une efficacité inversement proportionnelle à la durée de la maladie. Dès lors, l'implémentation d'un programme de dépistage néonatal s'est rapidement imposée comme une évidence médico-économique dans de nombreux pays. Dans ce contexte, nous avons initié un programme de dépistage néonatal pour la SMA en Belgique francophone et germanophone. En 2018, une étude pilote de trois ans visant à évaluer la faisabilité, l'efficacité et la rentabilité du screening a été initiée au sein du centre de dépistage de Liège. L'étude a récemment été étendue à l'ensemble de la Fédération Wallonie-Bruxelles (FWB) pour couvrir environ 55.000 naissances annuelles. Au 1er juin 2019, 35.000 bébés ont été dépistés et cinq nouveau-nés atteints de SMA ont été identifiés. Tous ont été immédiatement référés pour assurer leur prise en charge dans un centre de référence pour les maladies neuromusculaires. Une évaluation complète du programme aura lieu à l'issue de la phase pilote, afin d'envisager que la SMA soit reconnue comme maladie officielle du programme de dépistage néonatal en FWB.
Subject(s)
Muscular Atrophy, Spinal , Belgium/epidemiology , Humans , Infant , Infant, Newborn , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/epidemiology , Neonatal Screening , Pilot ProjectsABSTRACT
The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview of NGS capacities on DBS-extracted DNA but did not focus on the identification of specific disorders. We thus aimed to demonstrate that NGS was reliable for detecting pathogenic mutations on genomic material extracted from DBS. Assuming the future implementation of NGS technologies into newborn screening (NBS), we conducted a pilot study on fifteen patients with inherited metabolic disorders. Blood was collected from DBS. Whole-exome sequencing was performed, and sequences were analyzed with a specific focus on genes related to NBS. Results were compared to the known pathogenic mutations previously identified by Sanger sequencing. Causal mutations were readily characterized, and multiple polymorphisms have been identified. According to variant database prediction, an unexplained homozygote pathogenic mutation, unrelated to patient's disorder, was also found in one sample. While amount and quality of DBS-extracted DNA are adequate to identify causal mutations by NGS, bioinformatics analysis revealed critical drawbacks: coverage fluctuations between regions, difficulties in identifying insertions/deletions, and inconsistent reliability of database-referenced variants. Nevertheless, results of this study lead us to consider future perspectives regarding "next-generation" NBS.
Subject(s)
Dried Blood Spot Testing/methods , Genotype , Metabolic Diseases/genetics , Mutation/genetics , Computational Biology , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Infant, Newborn , Neonatal Screening , Pilot Projects , Polymorphism, Single Nucleotide , Reproducibility of Results , Exome SequencingABSTRACT
Recent advances in medical genomics open new perspectives for personalized medicine through the identification of genetic variants that influence drug response and/or the risk of side effects. Today, the clinical applications of pharmacogenetics remain scarce as a consequence of the cost and turn-around-time of genetic tests. However, a few tests are recommended, for instance before the prescription of some anti-cancer agents or the anti-retroviral agent abacavir. In the future, we will probably move either towards rapid targeted tests or towards a large screening, before any diagnosis, of all the genetic factors influencing the therapeutic response. In that case, physicians will have to consult the patient genomic data before drug prescription in order to personalize the choice of the therapeutic agent or its dosage. However, such a genomic approach brings economical and ethical questions and will require further progress in our capacity to interpret and store the personal genomic data without compromising their confidentiality.
Subject(s)
Genetic Testing/statistics & numerical data , Pharmacogenetics/methods , Precision Medicine/trends , Biomarkers, Pharmacological/analysis , Dideoxynucleosides/therapeutic use , Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/genetics , Genetic Testing/trends , Glucuronosyltransferase/deficiency , Glucuronosyltransferase/genetics , HLA-B Antigens/genetics , Humans , Neoplasms/genetics , Neoplasms/therapy , Precision Medicine/methods , Purine-Pyrimidine Metabolism, Inborn Errors/diagnosis , Purine-Pyrimidine Metabolism, Inborn Errors/geneticsABSTRACT
Today, the initiation of any medical treatment still raises questions about its efficacy and safety. Indeed, therapeutic responses vary over time and between individuals and are influenced by age, sex, other treatments and the pathology itself. Genetic factors are thought to be responsible for 20 to 95% of these individual variations. Recent advances in biotechnology, molecular genetics and genomics allow a better understanding of drug metabolism and action. Pharmacogenetics, compiling phenotypic and genotypic data, may lead to a more personalized treatment. To allow a better approach of pharmacogenetics and pharmacogenomics, we will define these two terms and describe their actual and future clinical application.
Subject(s)
Drug Therapy/trends , Pharmacogenetics , Drug Design , HumansABSTRACT
We describe a child with facial dysmorphism (trigonocephaly, epicanthus, upturned nose, small ears), thumb hypoplasia, micropenis, jejunal atresia and moderate mental retardation with dysphasia. Cytogenetic workup revealed high spontaneous level of chromosomal aberrations (without specific pattern and no quadriradial figures) and borderline to absent hypersensitivity to mitomycin C, making a diagnosis of Fanconi anemia unlikely. The child described here shares similarities with a small number of previous reports. We suggest to refer to this entity as episphalosomic syndrome. Episphalosomic syndrome shows some clinical overlap with Fanconi anemia, but lacks its cytogenetic hallmark. The hematological complications of Fanconi anemia have not been reported in this entity.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Chromosome Breakage , Fanconi Anemia/diagnosis , Fanconi Anemia/genetics , Abnormalities, Multiple/physiopathology , Adolescent , Child , Child, Preschool , Diagnosis, Differential , Face/abnormalities , Fanconi Anemia/physiopathology , Female , Humans , Infant, Newborn , Male , Mitomycin/pharmacology , Penis/abnormalities , Phenotype , Syndrome , Thumb/abnormalitiesABSTRACT
In South Belgium (Wallonia), the 'triple test' was introduced in 1990-1991, and is nowadays a widely accepted screening method for assessment of trisomy 21 risk in pregnancy. The 'triple test' is not regulated and can be freely performed by any biomedical lab, making epidemiological data unavailable. By contrast, cytogenetic investigations are limited to a few genetic centres, and accurate statistics can be easily built from their files. During the period 1984-1989, a total of 244 trisomy 21 (1/876 pregnancies) were diagnosed in the Genetic Centres of Liège and Loverval, 42 (17%) of them prenatally. During the period 1993-1998, 294 trisomy 21 (1/704 pregnancies) were observed, 165 (56%) of which prenatally, and more than 90% of affected pregnancies were terminated. Even after correction for late foetal loss of trisomic foetuses, the difference is highly significant, and corresponds to a theoretical shift in the incidence of trisomy 21 at birth from 1/794 to 1/1606. As no remarkable progress occurred in other non-invasive prenatal screening procedures or general health care policies in Belgium, the most reasonable explanation is the use on a large scale of triple test by pregnant women, and the election of termination for most affected pregnancies.
