Aminoacyl‐tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting ...aminoacyl‐tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl‐tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer.
SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity.
Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.
Aminoacyl‐tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity.
Cutis laxa (CL) is a rare connective tissue disorder characterized by wrinkled, abundant and sagging skin, sometimes associated with systemic impairment. Biallelic alterations in latent transforming ...growth factor beta‐binding protein 4 gene (LTBP4) cause autosomal recessive type 1C cutis laxa (ARCL1C, MIM #613177). The present report describes the case of a 17‐months‐old girl with cutis laxa together with a literature review of previous ARCL1C cases. Based on proband main clinical signs (cutis laxa and pulmonary emphysema), clinical exome sequencing (CES) was performed and showed a new nine base‐pairs homozygous in‐frame deletion in LTBP4 gene. RT‐PCR and cDNA Sanger sequencing were performed in order to clarify its impact on RNA. This report demonstrates that a genetic alteration in the EGF‐like 14 domain calcium‐binding motif of LTBP4 gene is likely responsible for cutis laxa in our patient.
The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a ...retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0–12.0) with 43% of males (55/128), and the median disease duration was 7 months (IQR 1–47). In the whole analysis, the CES diagnostic yield was 55% (70/128). The median test-to-report time was 5 months (IQR 4–7). According to CES indications, the CES diagnostic yields were 81% (21/26) for hyperlipidemia, 75% (6/8) for osteogenesis imperfecta, 64% (25/39) for metabolic disorders, 39% (10/26) for neurological disorders, and 28% (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation.
Graphic abstract
Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients’ subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0).
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Extracellular vesicles (EV) are emergent therapeutic effectors that have reached clinical trial investigation. To translate EV-based therapeutic to clinic, the challenge is to ...demonstrate quality, safety, and efficacy, as required for any medicinal product. EV research translation into medicinal products is an exciting and challenging perspective. Recent papers, provide important guidance on regulatory aspects of pharmaceutical development, defining EVs for therapeutic applications and critical considerations for the development of potency tests. In addition, the ISEV Task Force on Regulatory Affairs and Clinical Use of EV-based Therapeutics as well as the Exosomes Committee from the ISCT are expected to contribute in an active way to the development of EV-based medicinal products by providing update on the scientific progress in EVs field, information to patients and expert resource network for regulatory bodies. The contribution of our work group “Extracellular Vesicle translatiOn to clinicaL perspectiVEs – EVOLVE France”, created in 2020, can be positioned in complement to all these important initiatives. Based on complementary scientific, technical, and medical expertise, we provide EV-specific recommendations for manufacturing, quality control, analytics, non-clinical development, and clinical trials, according to current European legislation. We especially focus on early phase clinical trials concerning immediate needs in the field. The main contents of the investigational medicinal product dossier, marketing authorization applications, and critical guideline information are outlined for the transition from research to clinical development and ultimate market authorization.
Background
STUB1
has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in
STUB1
are now ...considered a frequent cause of cerebellar ataxia.
Objective
We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.
Methods
Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).
Results
Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with
STUB1
-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).
Conclusion
Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with
STUB1
pathogenic variations, we insist on the difficulty of genetic counselling in
STUB1
-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.
Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1∗01:02-DQB1∗06:02 (DQ0602) that very few ...non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1∗01:03-DPB1∗04:02 (DP0402; odds ratio OR = 0.51 0.38–0.67, p = 1.01 × 10−6) and HLA-DPA1∗01:03-DPB1∗04:01 (DP0401; OR = 0.61 0.47–0.80, p = 2.07 × 10−4) and predisposing effects of HLA-DPB1∗05:01 in Asians (OR = 1.76 1.34–2.31, p = 4.71 × 10−05). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 0.38–0.55 p = 8.99 × 10−17) and DP0501 (OR = 1.38 1.18–1.61, p = 7.11 × 10−5). HLA-class-II-independent associations with HLA-A∗11:01 (OR = 1.32 1.13–1.54, p = 4.92 × 10−4), HLA-B∗35:03 (OR = 1.96 1.41–2.70, p = 5.14 × 10−5), and HLA-B∗51:01 (OR = 1.49 1.25–1.78, p = 1.09 × 10−5) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.
Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number ...variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported.
This retrospective study examined 1641 CGH arrays performed over 8 years (2010-2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria.
Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size.
This study's high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.
We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS‐CoV‐2 infection, improving data interpretation and predicting key ...targets of intervention. Here, we describe a large‐scale community effort to build an open access, interoperable and computable repository of COVID‐19 molecular mechanisms. The COVID‐19 Disease Map (C19DMap) is a graphical, interactive representation of disease‐relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph‐based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS‐CoV‐2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID‐19 or similar pandemics in the long‐term perspective.
SYNOPSIS
COVID‐19 Disease Map is a large‐scale collection of curated computational models and diagrams of molecular mechanisms involved in SARS‐CoV‐2 infection. The map supports the computational exploration of pathways affected by the virus.
COVID‐19 Disease Map was built by over 20 independent biocuration teams and harmonised using systems biology standards.
Biocuration efforts were assisted by the systematic use of text‐ and AI‐assisted mining of relevant bioinformatic databases and platforms.
Case studies illustrate the applications of the map for visual exploration and computational analysis of SARS‐CoV‐2 pathways in combination with omic data.
The map is an open‐access effort, with all content and code shared in public repositories.
COVID‐19 Disease Map is a large‐scale collection of curated computational models and diagrams of molecular mechanisms involved in SARS‐CoV‐2 infection. The map supports the computational exploration of pathways affected by the virus.
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