We study the out-of-equilibrium dynamics of a weakly interacting one-dimensional Bose gas in a box trap, subjected to a drive realized by a periodically oscillating linear potential. After a transient regime, the gas reaches a quasi-steady state, characterized by the presence of several solitons. At weak driving amplitude, the solitons are only weakly perturbed by one another, while at strong driving amplitude a regime analogous to turbulence is reached, where the solitons are strongly intertwined with each other. We show that a hallmark of both regimes can be found in the momentum distribution, which displays a power-law decay n(k) ∼ k^-2 at weak driving amplitude and n(k) ∼ k^-α with a power-law exponent α∈ [7,9] at large amplitude. We further characterize each of the two regimes by following the space-time maps and characterizing the solitons using the inverse scattering transform. The protocol analyzed in this study is amenable to experimental realization in current experimental setups.

Titinopathies are complex neuromuscular disorders with multiple phenotypes. The gene's size, comprising 364 exons, as well as the protein's size of 3.8 MDa and its extensive network of protein interactors, are key factors underlying this complexity. Various phenotypes characterize titinopathies, and this study focuses on two of them: arthrogryposis and myofibrillar myopathies. The protein deregulations associated with these two phenotypes remain unknown or have been minimally explored; however, understanding these consequences is essential for better characterizing the pathophysiological aspects of these titinopathies.The objective was to analyze protein deregulations in two cohorts of French patients with titinopathies exhibiting the arthrogryposis and myofibrillar myopathy phenotypes, and to compare them with control individuals. Protein extracts were obtained from muscle biopsies of patients, and changes in protein levels within these two groups were analyzed by mass spectrometry. The results indicate specific deregulations in each group. The networks analyzed revealed deregulation of proteins involved in fibrosis mechanisms or in the actomyosin complex for the arthrogryposis phenotype. Regulation of the muscle contraction system through deregulation of proteins involved in the cytoskeleton is impacted in patients with myofibrillar myopathy. The proteins that are quantitatively abnormal in these two groups also provide insights into the major signaling networks disrupted in titinopathies. These findings will contribute to a more precise characterization of titinopathies, enabling the identification of phenotype-specific biomarkers and potentially guiding the search for targeted therapies for these neuromuscular disorders.

Tubulinopathies encompass a wide spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, hereditary spastic ataxia, and more recently, an isolated report of congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified 13 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, affected individuals in 17 families presented with a primary axial myopathy without any identified CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness, establishing the first documented association between TUBA4A variants and multisystem proteinopathy. Our cohort exhibited diverse genotypes and associated inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had homozygous TUBA4A variants, where the biallelic genotype was found to be associated with the disease, and the heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous TUBA4A variants were classified as "isolated-sporadic cases" where parental samples were unavailable. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were also variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies revealed a range of pathologies, including myofibre size variation, myofibre atrophy, nemaline bodies, core-like regions, internal nuclei, and endomysial fibrosis. Immunohistochemical staining showed evidence of proteinopathy, with autophagic features and TUBA4A accumulation in patient myofibres. Complementary in silico and in vitro investigations suggested that the identified TUBA4A substitutions cause significant protein abnormalities and may differentially impact microtubule dynamics. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

PURPOSE:Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases. METHODS:We collected data from 11,072 individuals with suspected rare diseases and 7390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature. RESULTS:Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high cardiac percent spliced in exon (>80%), and 4 had an overt cardiomyopathy. CONCLUSION:This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in individuals with skeletal myopathy with het TTNtv. Establishing consensus on percent spliced in-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.

BACKGROUND:Titinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs in TTN have been reported without clear genotype-phenotype associations. METHODS:Our study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in the TTN gene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients' muscles and performed genotype-phenotype inheritance association study by combining the clinical and biological data of these eight families. RESULTS:Seven deletion-type CNVs in the TTN gene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype-phenotype associations of titinopathies. CONCLUSION:Identifying TTN CNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in the TTN gene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype-phenotype associations of titinopathies, mainly distal myopathy in most of the patients.

The implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of "actionable" genes in diagnostic situations, involving specific treatment and/or management. In our project, we carried out an objective assessment of the clinical actionability of genes involved in myopathies, for which only few data obtained methodologically exist to date. Using the ClinGen Actionability criteria, we scored the clinical actionability of all 199 genes implicated in myopathies published by FILNEMUS for the "National French consensus on gene Lists for the diagnosis of myopathies using next generation sequencing". We objectified that 63 myopathy genes were actionable with the currently available data. Among the 36 myopathy genes with the highest actionability scores, only 8 had been scored to date by ClinGen. The data obtained through these methodological tools are an important resource for strategic choices in diagnostic approaches and the management of genetic myopathies. The clinical actionability of genes has to be considered as an evolving concept, in relation to progresses in disease knowledge and therapeutic approaches.

We report on an experimental platform based on an atom chip encompassing a coplanar waveguide which enables the manipulation of a quantum gas of sodium atoms with strong microwave fields. We describe the production with this setup of a very elongated degenerate quantum gas with typically 106 atoms that can be prepared all along the crossover from the three-dimensional to the one-dimensional regime, depending on the atom number and trapping geometry. Using the microwave field radiated by the waveguide, we drive Rabi oscillations between the hyperfine ground states, with the atoms trapped at various distances from the waveguide. At the closest position explored, the field amplitude exceeds 5 G, corresponding to a Rabi frequency on the strongest transition larger than 6 MHz. This enables fast manipulation of the atomic internal state.

Congenital titinopathies reported to date show autosomal recessive inheritance and are caused by a variety of genomic variants, most of them located in metatranscript (MTT)-only exons. The aim of this study was to describe additional patients and establish robust genotype-phenotype associations in titinopathies. This study involved analyzing molecular, clinical, pathological, and muscle imaging features in 20 patients who had at least one pathogenic or likely pathogenic TTN variant in MTT-only exons, with onset occurring antenatally or in the early postnatal stages. The 20 patients with recessive inheritance exhibited a heterogeneous range of phenotypes. These included fetal lethality, progressive weakness, cardiac or respiratory complications, hyper-CKemia, or dystrophic muscle biopsies. MRI revealed variable abnormalities in different muscles. All patients presented severe congenital myopathy at birth, characterized by arthrogryposis (either multiplex or axial-distal) or neonatal hypotonia in most cases. This study provides detailed genotype-phenotype correlations in congenital titinopathies caused by mutations in MTT-only exons. The findings highlight the variability in clinical presentation and the severity of phenotypes associated with these specific genetic alterations. RNA-seq analyses provided valuable insights into the molecular consequences of TTN variants, particularly in relation to splicing defects and nonsense-mediated RNA decay. In conclusion, this study reinforces the genotype-phenotype correlations between congenital myopathies and variants in TTN MTT-only exons, improves their molecular diagnosis, and provides a better understanding of their pathophysiology.

We report the observation of the melting of a vortex lattice in a fast rotating quasi-two dimensional Bose gas, under the influence of thermal fluctuations. We image the vortex lattice after a time-of-flight expansion, for increasing rotation frequency at constant atom number and temperature. We detect the vortex positions and study the order of the lattice using the pair correlation function and the orientational correlation function. We evidence the melting transition by an abrupt change in the decay of orientational correlations, associated to a proliferation of dislocations. Our findings are consistent with the hexatic to liquid transition in the KTHNY scenario for two-dimensional melting.

SpliceAI is an open-source deep learning splicing prediction algorithm that has demonstrated in the past few years its high ability to predict splicing defects caused by DNA variations. However, its outputs present several drawbacks: (1) although the numerical values are very convenient for batch filtering, their precise interpretation can be difficult, (2) the outputs are delta scores which can sometimes mask a severe consequence, and (3) complex delins are most often not handled. We present here SpliceAI-visual, a free online tool based on the SpliceAI algorithm, and show how it complements the traditional SpliceAI analysis. First, SpliceAI-visual manipulates raw scores and not delta scores, as the latter can be misleading in certain circumstances. Second, the outcome of SpliceAI-visual is user-friendly thanks to the graphical presentation. Third, SpliceAI-visual is currently one of the only SpliceAI-derived implementations able to annotate complex variants (e.g., complex delins). We report here the benefits of using SpliceAI-visual and demonstrate its relevance in the assessment/modulation of the PVS1 classification criteria. We also show how SpliceAI-visual can elucidate several complex splicing defects taken from the literature but also from unpublished cases. SpliceAI-visual is available as a Google Colab notebook and has also been fully integrated in a free online variant interpretation tool, MobiDetails ( https://mobidetails.iurc.montp.inserm.fr/MD ).

We report the observation of the controlled expansion of a two-dimensional quantum gas confined onto a curved shell-shaped surface. We start from the ellipsoidal geometry of a dressed quadrupole trap and introduce a novel gravity compensation mechanism enabling to explore the full ellipsoid. The zero-point energy of the transverse confinement manifests itself by the spontaneous emergence of an annular shape in the atomic distribution. The experimental results are compared with the solution of the three-dimensional Gross-Pitaevskii equation and with a two-dimensional semi-analytical model. This work evidences how a hidden dimension can affect dramatically the embedded low-dimensional system by inducing a change of topology.

Titin protein is responsible for muscle elasticity. The TTN gene, composed of 364 exons, is subjected to extensive alternative splicing and leads to different isoforms expressed in skeletal and cardiac muscle. Variants in TTN are responsible for myopathies with a wide phenotypic spectrum and autosomal dominant or recessive transmission. The I-band coding domain, highly subject to alternative splicing, contains a three-zone block of repeated sequences with 99% homology. Sequencing and localization of variants in these areas are complex when using short-reads sequencing, a second-generation sequencing technique. We have implemented a protocol based on the third-generation sequencing technology (long-reads sequencing). This new method allows us to localize variants in these repeated areas to improve the diagnosis of TTN-related myopathies and offer the analysis of relatives in postnatal or in prenatal screening.

Next generation sequencing (NGS) is strategically used for genetic diagnosis in patients with Charcot–Marie–Tooth disease (CMT) and related disorders called non-syndromic inherited peripheral neuropathies (NSIPN) in this paper. With over 100 different CMT-associated genes involved and ongoing discoveries, an important interlaboratory diversity of gene panels exists at national and international levels. Here, we present the work of the French National Network for Rare Neuromuscular Diseases (FILNEMUS) genetic diagnosis section which coordinates the seven French diagnosis laboratories using NGS for peripheral neuropathies. This work aimed to establish a unique, simple and accurate gene classification based on literature evidence. In NSIPN, three subgroups were usually distinguished: (1) HMSN, Hereditary Motor Sensory Neuropathy, (2) dHMN, distal Hereditary Motor Neuropathy, and (3) HSAN, Hereditary Sensory Autonomic Neuropathy. First, we reported ClinGen evaluation, and second, for the genes not evaluated yet by ClinGen, we classified them as “definitive” if reported in at least two clinical publications and associated with one report of functional evidence, or “limited” otherwise. In total, we report a unique consensus gene list for NSIPN including the three subgroups with 93 genes definitive and 34 limited, which is a good rate for our gene’s panel for molecular diagnostic use.

Yanliang Guo, ∗ Emmanuel Mercado Gutierrez, David Rey, Thomas Badr, Aurélien Perrin, Laurent Longchambon, Vanderlei Salvador Bagnato, Hélène Perrin, and Romain Dubessy † Université Sorbonne Paris Nord, Laboratoire de Physique des Lasers, CNRS UMR 7538, F-93430, Villetaneuse, France Instituto de F́ısica de São Carlos, Universidade de São Paulo, CP 369, São Carlos, São Paulo, 13560-970, Brazil (Dated: May 28, 2021)

Diagnosis of myopathies is challenged by the high genetic heterogeneity and clinical overlap of the various etiologies. We previously reported a Next-Generation Sequencing strategy to identify genetic etiology in patients with undiagnosed Limb-Girdle Muscular Dystrophies, Congenital Myopathies, Congenital Muscular Dystrophies, Distal Myopathies, Myofibrillar Myopathies, and hyperCKemia or effort intolerance, using a large gene panel including genes classically associated with other entry diagnostic categories. In this study, we report the comprehensive clinical-biological strategy used to interpret NGS data in a cohort of 156 pediatric and adult patients, that included Copy Number Variants search, variants filtering and interpretation according to ACMG guidelines, segregation studies, deep phenotyping of patients and relatives, transcripts and protein studies, and multidisciplinary meetings. Genetic etiology was identified in 74 patients, a diagnostic yield (47.4%) similar to previous studies. We identified 18 patients (10%) with causative variants in different genes (ACTA1, RYR1, NEB, TTN, TRIP4, CACNA1S, FLNC, TNNT1, and PAPBN1) that resulted in milder and/or atypical phenotypes, with high intrafamilial variability in some cases. Mild phenotypes could mostly be explained by a less deleterious effect of variants on the protein. Detection of inter-individual variability and atypical phenotype-genotype associations is essential for precision medicine, patient care, and to progress in the understanding of the molecular mechanisms of myopathies.