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L'amyotrophie spinale infantile (SMA pour spinal muscular atrophy) liée au gène SMN1 est une maladie neuromusculaire d'origine génétique, de transmission autosomique récessive, touchant environ 120 nouveau-nés par an en France. Elle se décline en cinq types cliniques, le type le plus courant entraînant le décès de l'enfant avant l'âge de 18 mois en l'absence de traitement. Trois thérapies innovantes se sont révélées efficaces, particulièrement si elles sont administrées avant l'apparition des symptômes. Ainsi, plusieurs pays ont déjà instauré le dépistage néonatal (DNN) de la SMA. En France, le programme de DNN actuel concerne treize maladies et utilise des tests biochimiques. Le DNN de la SMA serait le premier à utiliser un test génétique en première intention. Le projet préfigurateur DEPISMA a pour objectif de démontrer la faisabilité de ce dépistage dans deux grandes régions françaises, les régions Grand-Est et Nouvelle-Aquitaine, en prévision d'un déploiement national. Au 10 septembre 2024, 117769 nouveau-nés ont été testés, soit un taux d'exhaustivité de 94 %. Onze patients atteints de SMA ont été dépistés, dont huit ont bénéficié d'une thérapie génique. Ces résultats, associés à l'avis favorable de la Haute Autorité de santé (HAS), devraient ouvrir la voie à la mise en œuvre d'un programme national de dépistage, prévu à partir de juin 2025. SMN1 gene-linked infantile spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder of genetic origin, affecting around 120 newborns a year in France. There are five clinical types, the most common leading to death before the age of 18 months if left untreated.Three innovative therapies have proved effective, particularly if administered before symptoms appear. Several countries have already introduced newborn screening (NBS) for SMA. In France, the current NBS program covers 13 diseases and uses biochemical tests.The SMA NBS would be the first to use a genetic test in first intention.The aim of the DEPISMA prefigurator project is to demonstrate the feasibility of this screening in two major French regions, Grand-Est and Nouvelle-Aquitaine, with a view to national deployment. As of September 10, 2024, 117,769 newborns have been tested, representing a completeness rate of 94 %. Eleven SMA patients have been identified, eight of whom were treated with gene therapy. These results, combined with the favorable opinion of the French National Authority for Health, should pave the way for the implementation of a national program, scheduled to start in June 2025. [ABSTRACT FROM AUTHOR]

Background Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. Methods Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. Results Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. Conclusion We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously. [ABSTRACT FROM AUTHOR]

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop's classification (Witkop, J Oral Pathol, 1988, 17, 547-553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative. Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management. Methods: Individuals presenting with so called "isolated" or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/). Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance. Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI ( CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop's AI classification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bloch-Zupan, Rey, Jimenez-Armijo, Kawczynski, Kharouf, O-Rare consortium, Dure-Molla, Noirrit, Hernandez, Joseph-Beaudin, Lopez, Tardieu, Thivichon-Prince, ERN Cranio Consortium, Dostalova, Macek, International Consortium, Alloussi, Qebibo, Morkmued, Pungchanchaikul, Orellana, Manière, Gérard, Bugueno and Laugel-Haushalter.)

Rare genetic disorders are often challenging to diagnose. Anomalies of tooth number, shape, size, mineralized tissue structure, eruption, and resorption may exist as isolated symptoms or diseases but are often part of the clinical synopsis of numerous syndromes (Bloch-Zupan A, Sedano H, Scully C. Dento/oro/craniofacial anomalies and genetics, 1st edn. Elsevier, Boston, MA, 2012). Concerning amelogenesis imperfecta (AI), for example, mutations in a number of genes have been reported to cause isolated AI, including AMELX, ENAM, KLK4, MMP20, FAM83H, WDR72, C4orf26, SLC24A4, and LAMB3. In addition, many other genes such as DLX3, CNNM4, ROGDI, FAM20A, STIM1, ORAI1, and LTBP3 have been shown to be involved in developmental syndromes with enamel defects. The clinical presentation of the enamel phenotype (hypoplastic, hypomineralized, hypomature, or a combination of severities) alone does not allow a reliable prediction of possible causative genetic mutations. Understanding the potential genetic cause(s) of rare diseases is critical for overall health management of affected patient. One effective strategy to reach a genetic diagnosis is to sequence a selected gene panel chosen for a determined range of phenotypes. Here we describe a laboratory protocol to set up a specific gene panel for orodental diseases.