Search

Copy number variations are the main genetic alterations associated with dystrophinopathies. Patients with in-frame deletions usually have a milder phenotype but a wilder clinical spectrum. While inter-familial phenotype variability is known to occur for specific deletions, phenotype divergence within a family is much less explored. The widespread use of array CGH as the primary tool in prenatal diagnosis has increased the number of incidental findings in the DMD gene and poses a challenge for establishing the prognosis and decision-making. We report 5 unrelated male fetuses with in-frame deletions in the DMD gene, detected as incidental findings in routine prenatal diagnosis using array CGH with exonic resolution. Familial segregation and clinical evaluation of potential carriers on the maternal side of the family, particularly male relatives, were performed in the five families. Males bearing the mutation were identified in each family, with phenotypes ranging from asymptomatic to isolated hyperckemia, tip-toe walking, language delay, or cardiac dysfunction, raising the question of whether some of the less specific symptoms are mutation-related. Given these complexities, especially in a prenatal context, it is crucial to implement a rapid and systematic multidisciplinary coordinated strategy to conduct a comprehensive and simultaneous genetic and clinical study of potential male carriers. This strategy, added to the careful review of the existing knowledge of specific genotype-phenotype correlations, should help in prenatal counseling. Collaborative, multicentric research, involving data on multiple pedigrees ascertained by such DMD prenatal findings is needed to more precisely define the phenotype associated with each specific mutation and its familial variability. [ABSTRACT FROM AUTHOR]

This article discusses the use of targeted magnetic resonance imaging (MRI) on parents to improve prenatal counseling for brain anomalies in fetuses. The study found that MRI conducted on at least one parent was relevant for prenatal counseling in five cases, with a definitive diagnosis reached in three cases. The results of the MRI were consistent with the ultrasound diagnosis in all cases and provided additional information in two cases. The authors conclude that this approach, known as TRIO-MRI, can be valuable in the prenatal diagnosis of certain brain anomalies. [Extracted from the article]

Objective: Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging., Methods: In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE., Results: We generated new RNA-seq data on TTN exons and identified genotype-phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case., Interpretation: This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions., Aim: To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND)., Methods: Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network., Results: Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice., Conclusions: This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions., Methods: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology., Findings: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases., Conclusions: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO)., Funding: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)