Publications by authors named "Massimiliano Rossi"

111 Publications

PHONI: Streamed Matching Statistics with Multi-Genome References.

Proc Data Compress Conf 2021 Mar 10;2021:193-202. Epub 2021 May 10.

U Florida Gainesville, USA.

Computing the matching statistics of patterns with respect to a text is a fundamental task in bioinformatics, but a formidable one when the text is a highly compressed genomic database. Bannai et al. gave an efficient solution for this case, which Rossi et al. recently implemented, but it uses two passes over the patterns and buffers a pointer for each character during the first pass. In this paper, we simplify their solution and make it streaming, at the cost of slowing it down slightly. This means that, first, we can compute the matching statistics of several long patterns (such as whole human chromosomes) in parallel while still using a reasonable amount of RAM; second, we can compute matching statistics online with low latency and thus quickly recognize when a pattern becomes incompressible relative to the database. Our code is available at https://github.com/koeppl/phoni.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/dcc50243.2021.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583545PMC
March 2021

Flow profiles near receding three-phase contact lines: influence of surfactants.

Soft Matter 2021 Nov 17;17(44):10090-10100. Epub 2021 Nov 17.

Max Planck Institute for Polymer Research, Ackermannweg 10, D-55128 Mainz, Germany.

The dynamics of wetting and dewetting is largely determined by the velocity field near the contact lines. For water drops it has been observed that adding surfactant decreases the dynamic receding contact angle even at a concentration much lower than the critical micelle concentration (CMC). To better understand why surfactants have such a drastic effect on drop dynamics, we constructed a dedicated setup on an inverted microscope, in which an aqueous drop is held stationary while the transparent substrate is moved horizontally. Using astigmatism particle tracking velocimetry, we track the 3D displacement of the tracer particles in the flow. We study how surfactants alter the flow dynamics near the receding contact line of a moving drop for capillary numbers in the order of 10. Even for surfactant concentrations far below the critical micelle concentration ( ≪ CMC) Marangoni stresses change the flow drastically. We discuss our results first in a 2D model that considers advective and diffusive surfactant transport and deduce estimates of the magnitude and scaling of the Marangoni stress from this. Modeling and experiment agree that a tiny gradient in surface tension of a few μN m is enough to alter the flow profile significantly. The variation of the Marangoni stress with the distance from the contact line suggests that the 2D advection-diffusion model has to be extended to a full 3D model. The effect is ubiquitous, since surfactant is present in many technical and natural dewetting processes either deliberately or as contamination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1sm01145fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597584PMC
November 2021

GGCX-related congenital combined vitamin K-dependent clotting factors deficiency-1: Description of a fetus with chondrodysplasia punctata.

Am J Med Genet A 2021 Sep 24. Epub 2021 Sep 24.

Hospices Civils de Lyon, Service de Génétique, Centre de Référence Anomalies du Développement et Centre de Compétence Maladies Osseuses Constitutionnelles, Groupement Hospitalier Est, Bron, France.

Congenital combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare autosomal recessive disease resulting in hemorrhagic symptoms usually associated with developmental disorders and bone abnormalities. Pathogenic variants in two genes encoding enzymes of the vitamin K cycle, GGCX and VKORC1, can lead to this disorder. We present the case of a male fetus with a brachytelephalangic chondrodysplasia punctata (CDP), absence of nasal bone, growth restriction, and bilateral ventriculomegaly at 18 weeks of gestation. Pathological examination showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses, and brain abnormalities suggestive of a brain hemorrhage. Two GGCX pathogenic variants inherited respectively from the mother and the father were identified. To our knowledge, this is the first prenatal description of VKCFD. Even if it remains a rare etiology, which is mostly described in children or adult patients, VKCFD should be considered in fetuses with CDP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62503DOI Listing
September 2021

10 years of CEMARA database in the AnDDI-Rares network: a unique resource facilitating research and epidemiology in developmental disorders in France.

Orphanet J Rare Dis 2021 08 4;16(1):345. Epub 2021 Aug 4.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Dijon, Dijon, France.

Background: In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation.

Methods: Since 2007, clinicians and researchers have reported the "minimum dataset (MDS)" for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses.

Results: Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient's home was 25.1 km (IQR = 6.3 km-64.2 km).

Conclusions: CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01957-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335940PMC
August 2021

Erotomania and phenotypic continuum in a family frameshift variant of AUTS2: a case report and review.

BMC Psychiatry 2021 07 17;21(1):360. Epub 2021 Jul 17.

GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, le Vinatier Hospital Center and EDR-Psy Team (National Center for Scientific Research and Lyon 1 Claude Bernard University), Lyon, France.

Background: Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene.

Case Presentation: The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant.

Conclusions: The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12888-021-03342-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285776PMC
July 2021

Quantum control of a nanoparticle optically levitated in cryogenic free space.

Nature 2021 07 14;595(7867):378-382. Epub 2021 Jul 14.

Photonics Laboratory, ETH Zürich, Zürich, Switzerland.

Tests of quantum mechanics on a macroscopic scale require extreme control over mechanical motion and its decoherence. Quantum control of mechanical motion has been achieved by engineering the radiation-pressure coupling between a micromechanical oscillator and the electromagnetic field in a resonator. Furthermore, measurement-based feedback control relying on cavity-enhanced detection schemes has been used to cool micromechanical oscillators to their quantum ground states. In contrast to mechanically tethered systems, optically levitated nanoparticles are particularly promising candidates for matter-wave experiments with massive objects, since their trapping potential is fully controllable. Here we optically levitate a femtogram (10 grams) dielectric particle in cryogenic free space, which suppresses thermal effects sufficiently to make the measurement backaction the dominant decoherence mechanism. With an efficient quantum measurement, we exert quantum control over the dynamics of the particle. We cool its centre-of-mass motion by measurement-based feedback to an average occupancy of 0.65 motional quanta, corresponding to a state purity of 0.43. The absence of an optical resonator and its bandwidth limitations holds promise to transfer the full quantum control available for electromagnetic fields to a mechanical system. Together with the fact that the optical trapping potential is highly controllable, our experimental platform offers a route to investigating quantum mechanics at macroscopic scales.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03617-wDOI Listing
July 2021

Flavonoids: A Myth or a Reality for Cancer Therapy?

Molecules 2021 Jun 11;26(12). Epub 2021 Jun 11.

Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy.

Nutraceuticals are biologically active molecules present in foods; they can have beneficial effects on health, but they are not available in large enough quantities to perform this function. Plant metabolites, such as polyphenols, are widely diffused in the plant kingdom, where they play fundamental roles in plant development and interactions with the environment. Among these, flavonoids are of particular interest as they have significant effects on human health. In vitro and/or in vivo studies described flavonoids as essential nutrients for preventing several diseases. They display broad and promising bioactivities to fight cancer, inflammation, bacterial infections, as well as to reduce the severity of neurodegenerative and cardiovascular diseases or diabetes. Therefore, it is not surprising that interest in flavonoids has sharply increased in recent years. More than 23,000 scientific publications on flavonoids have described the potential anticancer activity of these natural molecules in the last decade. Studies, in vitro and in vivo, show that flavonoids exhibit anticancer properties, and many epidemiological studies confirm that dietary intake of flavonoids leads to a reduced risk of cancer. This review provides a glimpse of the mechanisms of action of flavonoids on cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26123583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230897PMC
June 2021

Pan-genomic matching statistics for targeted nanopore sequencing.

iScience 2021 Jun 8;24(6):102696. Epub 2021 Jun 8.

Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.

Nanopore sequencing is an increasingly powerful tool for genomics. Recently, computational advances have allowed nanopores to sequence in a targeted fashion; as the sequencer emits data, software can analyze the data in real time and signal the sequencer to eject "nontarget" DNA molecules. We present a novel method called SPUMONI, which enables rapid and accurate targeted sequencing using efficient pan-genome indexes. SPUMONI uses a compressed index to rapidly generate exact or approximate matching statistics in a streaming fashion. When used to target a specific strain in a mock community, SPUMONI has similar accuracy as minimap2 when both are run against an index containing many strains per species. However SPUMONI is 12 times faster than minimap2. SPUMONI's index and peak memory footprint are also 16 to 4 times smaller than those of minimap2, respectively. This could enable accurate targeted sequencing even when the targeted strains have not necessarily been sequenced or assembled previously.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237286PMC
June 2021

On Infinite Prefix Normal Words.

Theor Comput Sci 2021 Mar 11;859:134-148. Epub 2021 Jan 11.

Department of Computer and Information Science and Engineering, University of Florida, Gainesville, FL, United States.

Prefix normal words are binary words with the property that no factor has more 1s than the prefix of the same length. Finite prefix normal words were introduced in [Fici and Lipták, DLT 2011]. In this paper, we study infinite prefix normal words and explore their relationship to some known classes of infinite binary words. In particular, we establish a connection between prefix normal words and Sturmian words, between prefix normal words and abelian complexity, and between prefix normality and lexicographic order.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcs.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219218PMC
March 2021

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Pediatric Neurology Department, Lyon University Hospital, 69500 Bron, France.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab219DOI Listing
June 2021

Fast and efficient Rmap assembly using the Bi-labelled de Bruijn graph.

Algorithms Mol Biol 2021 May 25;16(1). Epub 2021 May 25.

Department of Computer and Information Science and Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, USA.

Genome wide optical maps are high resolution restriction maps that give a unique numeric representation to a genome. They are produced by assembling hundreds of thousands of single molecule optical maps, which are called Rmaps. Unfortunately, there are very few choices for assembling Rmap data. There exists only one publicly-available non-proprietary method for assembly and one proprietary software that is available via an executable. Furthermore, the publicly-available method, by Valouev et al. (Proc Natl Acad Sci USA 103(43):15770-15775, 2006), follows the overlap-layout-consensus (OLC) paradigm, and therefore, is unable to scale for relatively large genomes. The algorithm behind the proprietary method, Bionano Genomics' Solve, is largely unknown. In this paper, we extend the definition of bi-labels in the paired de Bruijn graph to the context of optical mapping data, and present the first de Bruijn graph based method for Rmap assembly. We implement our approach, which we refer to as RMAPPER, and compare its performance against the assembler of Valouev et al. (Proc Natl Acad Sci USA 103(43):15770-15775, 2006) and Solve by Bionano Genomics on data from three genomes: E. coli, human, and climbing perch fish (Anabas Testudineus). Our method was able to successfully run on all three genomes. The method of Valouev et al. (Proc Natl Acad Sci USA 103(43):15770-15775, 2006) only successfully ran on E. coli. Moreover, on the human genome RMAPPER was at least 130 times faster than Bionano Solve, used five times less memory and produced the highest genome fraction with zero mis-assemblies. Our software, RMAPPER is written in C++ and is publicly available under GNU General Public License at https://github.com/kingufl/Rmapper .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13015-021-00182-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147420PMC
May 2021

Modeling and Observation of Nonlinear Damping in Dissipation-Diluted Nanomechanical Resonators.

Phys Rev Lett 2021 Apr;126(17):174101

Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark and Center for Hybrid Quantum Networks (Hy-Q), Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen, Denmark.

Dissipation dilution enables extremely low linear loss in stressed, high aspect ratio nanomechanical resonators, such as strings or membranes. Here, we report on the observation and theoretical modeling of nonlinear dissipation in such structures. We introduce an analytical model based on von Kármán theory, which can be numerically evaluated using finite-element models for arbitrary geometries. We use this approach to predict nonlinear loss and (Duffing) frequency shift in ultracoherent phononic membrane resonators. A set of systematic measurements with silicon nitride membranes shows good agreement with the model for low-order soft-clamped modes. Our analysis also reveals quantitative connections between these nonlinearities and dissipation dilution. This is of interest for future device design and can provide important insight when diagnosing the performance of dissipation dilution in an experimental setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevLett.126.174101DOI Listing
April 2021

Clinical delineation of SETBP1 haploinsufficiency disorder.

Eur J Hum Genet 2021 Aug 19;29(8):1198-1205. Epub 2021 Apr 19.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

SETBP1 haploinsufficiency disorder (MIM#616078) is caused by haploinsufficiency of SETBP1 on chromosome 18q12.3, but there has not yet been any systematic evaluation of the major features of this monogenic syndrome, assessing penetrance and expressivity. We describe the first comprehensive study to delineate the associated clinical phenotype, with findings from 34 individuals, including 24 novel cases, all of whom have a SETBP1 loss-of-function variant or single (coding) gene deletion, confirmed by molecular diagnostics. The most commonly reported clinical features included mild motor developmental delay, speech impairment, intellectual disability, hypotonia, vision impairment, attention/concentration deficits, and hyperactivity. Although there is a mild overlap in certain facial features, the disorder does not lead to a distinctive recognizable facial gestalt. As well as providing insight into the clinical spectrum of SETBP1 haploinsufficiency disorder, this reports puts forward care recommendations for patient management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-021-00888-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385049PMC
August 2021

How Euglena gracilis swims: Flow field reconstruction and analysis.

Phys Rev E 2021 Feb;103(2-1):023102

SISSA-International School for Advanced Studies, Via Bonomea 265, 34136 Trieste, Italy.

Euglena gracilis is a unicellular organism that swims by beating a single anterior flagellum. We study the nonplanar waveforms spanned by the flagellum during a swimming stroke and the three-dimensional flows that they generate in the surrounding fluid. Starting from a small set of time-indexed images obtained by optical microscopy on a swimming Euglena cell, we construct a numerical interpolation of the stroke. We define an optimal interpolation (which we call synthetic stroke) by minimizing the discrepancy between experimentally measured velocities (of the swimmer) and those computed by solving numerically the equations of motion of the swimmer driven by the trial interpolated stroke. The good match we obtain between experimentally measured and numerically computed trajectories provides a first validation of our synthetic stroke. We further validate the procedure by studying the flow velocities induced in the surrounding fluid. We compare the experimentally measured flow fields with the corresponding quantities computed by solving numerically the Stokes equations for the fluid flow, in which the forcing is provided by the synthetic stroke, and find good matching. Finally, we use the synthetic stroke to derive a coarse-grained model of the flow field resolved in terms of a few dominant singularities. The far field is well approximated by a time-varying Stresslet, and we show that the average behavior of Euglena during one stroke is that of an off-axis puller. The reconstruction of the flow field closer to the swimmer body requires a more complex system of singularities. A system of two Stokeslets and one Rotlet, that can be loosely associated with the force exerted by the flagellum, the drag of the body, and a torque to guarantee rotational equilibrium, provides a good approximation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevE.103.023102DOI Listing
February 2021

Enhancement of Tolerance to High Saline Conditions by Seed Priming.

Plants (Basel) 2021 Feb 20;10(2). Epub 2021 Feb 20.

Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy.

Plants grown in saline soils undergo osmotic and oxidative stresses, affecting growth and photosynthesis and, consequently, the yield. Therefore, the increase in soil salinity is a major threat to crop productivity worldwide. Plant's tolerance can be ameliorated by applying simple methods that induce them to adopt morphological and physiological adjustments to counteract stress. In this work, we evaluated the effects of seed priming on salt stress response in three cultivars of rapeseed ( L.) that had different tolerance levels. Seed chemical priming was performed with 2.5 mM spermine (SPM), 5 mM spermidine (SPD), 40 mM NaCl and 2.5 mM Ca (NO). Primed and not primed seeds were sown on saline and not saline (controls) media, and morphological and physiological parameters were determined. Since SPD treatment was effective in reducing salinity negative effects on growth, membrane integrity and photosynthetic pigments, we selected this priming to further investigate plant salt stress response. The positive effects of this seed treatment on growth and physiological responses were evident when primed plants were compared to not primed ones, grown under the same saline conditions. SPD priming ameliorated the tolerance towards saline stress, in a genotype-independent manner, by increasing photosynthetic pigments, proline amounts and antioxidant responses in all cultivars exposed to salt. These results may open new perspectives for crop productivity in the struggle against soil salinization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/plants10020403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923807PMC
February 2021

Sensenbrenner syndrome: a further challenge in evaluating sagittal synostosis and a need for a multidisciplinary approach.

Childs Nerv Syst 2021 05 19;37(5):1695-1701. Epub 2021 Feb 19.

Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France.

Background: Sensenbrenner syndrome, also known as cranioectodermal dysplasia (CED), is a genetically heterogeneous ciliopathy, characterized by dysmorphic features including dolichocephaly (with inconstant sagittal craniosynostosis), chronic kidney disease (CKD), hepatic fibrosis, retinitis pigmentosa, and brain abnormalities, with a partial clinical overlap with other ciliopathies.

Patients And Methods: A retrospective review of four children with Sensenbrenner syndrome treated at the Femme Mère Enfant University Hospital of Lyon from 2005 to 2020 was conducted.

Results: Variants in WDR35 or WDR19 were found in all children. Two of them underwent surgery for a scaphocephaly in the first months of life. All patients developed CKD leading to end-stage renal disease during the first/second decades.

Discussion: The diagnosis of scaphocephaly may precede the diagnosis of the underlying Sensenbrenner syndrome, thus highlighting the importance of a systematic multidisciplinary assessment and follow-up for craniosynostoses, in order to identify syndromic forms requiring specific management. In Sensenbrenner syndrome, patients' management should be coordinated by multidisciplinary teams of reference centers for rare diseases, with expertise in the management of craniofacial malformations as well as rare skeletal and renal disorders. Indeed, a prompt etiological diagnosis will result in an early diagnosis of multisystemic complications, notably renal involvement, thus improving global prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00381-021-05075-1DOI Listing
May 2021

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Clin Genet 2021 05 20;99(5):650-661. Epub 2021 Jan 20.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13918DOI Listing
May 2021

Growth charts in Cockayne syndrome type 1 and type 2.

Eur J Med Genet 2021 Jan 20;64(1):104105. Epub 2020 Nov 20.

Service de Pédiatrie 1, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Laboratoire de Génétique médicale, INSERM U1112, Institut de génétique médicale d'Alsace, Faculté de Médecine de Strasbourg, Hôpitaux Universitaires de Strasbourg, France.

Cockayne syndrome (CS) is a multisystem degenerative disorder divided in 3 overlapping subtypes, with a continuous phenotypic spectrum: CS2 being the most severe form, CS1 the classical form and CS3 the late-onset form. Failure to thrive and growth difficulties are among the most consistent features of CS, leaving affected individuals vulnerable to numerous medical complications, including adverse effects of undernutrition, abrupt overhydration and overfeeding. There is thus a significant need for specific growth charts. We retrospectively collected growth parameters from genetically-confirmed CS1 and CS2 patients, used the GAMLSS package to construct specific CS growth charts compared to healthy children from WHO and CDC databases. Growth data were obtained from 88 CS patients with a total of 1626 individual growth data points. 49 patients were classified as CS1 and 39 as CS2 with confirmed mutations in CSB/ERCC6, CSA/ERCC8 or ERCC1 genes. Individuals with CS1 initially have normal growth parameters; microcephaly occurs from 2 months whereas onset of weight and height restrictions appear later, between 5 and 22 months. In CS2, growth parameters are already below standard references at birth or drop below the 5th percentile before 3 months. Microcephaly is the first parameter to show a delay, appearing around 2 months in CS1 and at birth in CS2. Height and head circumference are more severely affected in CS2 compared to CS1 whereas weight curves are similar in CS1 and CS2 patients. These new growth charts will serve as a practical tool to improve the nutritional management of children with CS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2020.104105DOI Listing
January 2021

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

Genet Med 2021 02 4;23(2):363-373. Epub 2020 Nov 4.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.

Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.

Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.

Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-00988-9DOI Listing
February 2021

Normal intellectual skills in patients with Rhombencephalosynapsis.

Eur J Paediatr Neurol 2020 Nov 30;29:92-100. Epub 2020 Sep 30.

Department of Pediatric Neurology, Competence Centre for Cerebellar Malformations, Lyon University Hospital, F-69677, Bron, France; University Lyon 1, F-69008, Lyon, France. Electronic address:

Objectives: Rhombencephalosynapsis (RES) is a very rare cerebellar malformation. Neurodevelopmental outcome of apparently isolated RES remains poorly documented and standardized cognitive assessment, reported in only nine published cases so far, is lacking. Prenatal counselling is challenging considering the uncertain prognosis of isolated RES. The aim of this study was to focus on cognitive and motor outcome of isolated RES with a clinical description of six new cases and a detailed review of the literature.

Methods: A single-centre retrospective study of all RES patients over a 15-year period. Ataxia and fine motor skills were scored using a five-grade scale, according to the degree of disturbance of daily living. Intelligence Quotient (IQ) was established according to age-related Weschler Intelligence Scales. A systematic literature review included published cases with relevant outcome data.

Results: Six new cases of apparently isolated RES were reported, including three diagnosed in prenatal settings. The onset age for walking was delayed in four patients. Three patients had head shaking and three had a strabismus. One patient had a mild motor disability, one had subtle ataxia that did not impair daily life and four patients had a normal neurological examination at the last visit. Intellectual abilities were normal in all patients (full IQ score from 90 to 142), although three had ADHD. All received standard schooling. Based on these six new cases, as well as cases from 12 publications in the literature, a total of 28 patients with non-syndromic RES were analysed. Concerning motor outcome, 72% had no complaint or minimal impairment, 16% moderate and 12% severe impairment. Concerning cognitive outcome, 68% had normal cognitive skills, 18% borderline intellectual functioning and 14% moderate to severe disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2020.09.007DOI Listing
November 2020

Experimental Assessment of Entropy Production in a Continuously Measured Mechanical Resonator.

Phys Rev Lett 2020 Aug;125(8):080601

Centre for Theoretical Atomic, Molecular, and Optical Physics, School of Mathematics and Physics, Queens University, Belfast BT7 1NN, United Kingdom.

The information on a quantum process acquired through measurements plays a crucial role in the determination of its nonequilibrium thermodynamic properties. We report on the experimental inference of the stochastic entropy production rate for a continuously monitored mesoscopic quantum system. We consider an optomechanical system subjected to continuous displacement Gaussian measurements and characterize the entropy production rate of the individual trajectories followed by the system in its stochastic dynamics, employing a phase-space description in terms of the Wigner entropy. Owing to the specific regime of our experiment, we are able to single out the informational contribution to the entropy production arising from conditioning the state on the measurement outcomes. Our experiment embodies a significant step towards the demonstration of full-scale control of fundamental thermodynamic processes at the mesoscopic quantum scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevLett.125.080601DOI Listing
August 2020

Author Correction: Entanglement of propagating optical modes via a mechanical interface.

Nat Commun 2020 Sep 7;11(1):4538. Epub 2020 Sep 7.

Niels Bohr Institute, University of Copenhagen, 2100, Copenhagen, Denmark.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18516-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476922PMC
September 2020

Mandibular-pelvic-patellar syndrome is a novel PITX1-related disorder due to alteration of PITX1 transactivation ability.

Hum Mutat 2020 09 15;41(9):1499-1506. Epub 2020 Jul 15.

Service de Génétique, Centre de Référence Anomalies du Développement et Centre de Compétences Maladies Osseuses Constitutionnelles, Hospices Civils de Lyon, Bron, France.

PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1-related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a "lower limb" appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with the Pitx1-/- mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused by TBX4 haploinsufficiency, and with the phenotypic spectrum caused by SOX9 anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum of PITX1-related disorders and suggest a common pattern of developmental abnormalities in disorders of the PITX1-TBX4-SOX9 signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.24070DOI Listing
September 2020

Telemedicine strategy of the European Reference Network ITHACA for the diagnosis and management of patients with rare developmental disorders.

Orphanet J Rare Dis 2020 04 25;15(1):103. Epub 2020 Apr 25.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, M13 9WL, UK.

Background: The European Reference Networks, ERNs, are virtual networks for healthcare providers across Europe to collaborate and share expertise on complex or rare diseases and conditions. As part of the ERNs, the Clinical Patient Management System, CPMS, a secure digital platform, was developed to allow and facilitate web-based, clinical consultations between submitting clinicians and relevant international experts. The European Reference Network on Intellectual Disability, TeleHealth and Congenital Anomalies, ERN ITHACA, was formed to harness the clinical and diagnostic expertise in the sector of rare, multiple anomaly and/or intellectual disability syndromes, chromosome disorders and undiagnosed syndromic disorders. We present the first year results of CPMS use by ERN ITHACA as an example of a telemedicine strategy for the diagnosis and management of patients with rare developmental disorders.

Results: ERN ITHACA ranked third in telemedicine activity amongst 24 European networks after 12 months of using the CPMS. Information about 28 very rare cases from 13 different centres across 7 countries was shared on the platform, with diagnostic or other management queries. Early interaction with patient support groups identified data protection as of primary importance in adopting digital platforms for patient diagnosis and care. The first launch of the CPMS was built to accommodate the needs of all ERNs. The ERN ITHACA telemedicine process highlighted a need to customise the CPMS with network-specific requirements. The results of this effort should enhance the CPMS utility for telemedicine services and ERN-specific care outcomes.

Conclusions: We present the results of a long and fruitful process of interaction between the ERN ITHACA network lead team and EU officials, software developers and members of 38 EU clinical genetics centres to organise and coordinate direct e-healthcare through a secure, digital platform. The variability of the queries in just the first 28 cases submitted to the ERN ITHACA CPMS is a fair representation of the complexity and rarity of the patients referred, but also proof of the sophisticated and variable service that could be provided through a structured telemedicine approach for patients and families with rare developmental disorders. Web-based approaches are likely to result in increased accessibility to clinical genomic services.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-1349-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183125PMC
April 2020

Entanglement of propagating optical modes via a mechanical interface.

Nat Commun 2020 Feb 18;11(1):943. Epub 2020 Feb 18.

Niels Bohr Institute, University of Copenhagen, 2100, Copenhagen, Denmark.

Many applications of quantum information processing (QIP) require distribution of quantum states in networks, both within and between distant nodes. Optical quantum states are uniquely suited for this purpose, as they propagate with ultralow attenuation and are resilient to ubiquitous thermal noise. Mechanical systems are then envisioned as versatile interfaces between photons and a variety of solid-state QIP platforms. Here, we demonstrate a key step towards this vision, and generate entanglement between two propagating optical modes, by coupling them to the same, cryogenic mechanical system. The entanglement persists at room temperature, where we verify the inseparability of the bipartite state and fully characterize its logarithmic negativity by homodyne tomography. We detect, without any corrections, correlations corresponding to a logarithmic negativity of E = 0.35. Combined with quantum interfaces between mechanical systems and solid-state qubit processors, this paves the way for mechanical systems enabling long-distance quantum information networking over optical fiber networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-14768-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028980PMC
February 2020

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature.

Eur J Hum Genet 2020 06 31;28(6):770-782. Epub 2020 Jan 31.

Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, OR, USA.

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-0571-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253452PMC
June 2020

Observing and Verifying the Quantum Trajectory of a Mechanical Resonator.

Phys Rev Lett 2019 Oct;123(16):163601

Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen, Denmark.

Continuous weak measurement allows localizing open quantum systems in state space and tracing out their quantum trajectory as they evolve in time. Efficient quantum measurement schemes have previously enabled recording quantum trajectories of microwave photon and qubit states. We apply these concepts to a macroscopic mechanical resonator, and we follow the quantum trajectory of its motional state conditioned on a continuous optical measurement record. Starting with a thermal mixture, we eventually obtain coherent states of 78% purity-comparable to a displaced thermal state of occupation 0.14. We introduce a retrodictive measurement protocol to directly verify state purity along the trajectory, and we furthermore observe state collapse and decoherence. This opens the door to measurement-based creation of advanced quantum states, as well as potential tests of gravitational decoherence models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevLett.123.163601DOI Listing
October 2019

Interfacial flows in sessile evaporating droplets of mineral water.

Phys Rev E 2019 Sep;100(3-1):033103

Institute of Fluid Mechanics and Aerodynamics, Bundeswehr University Munich, 85577 Neubiberg, Germany.

Liquid flow in sessile evaporating droplets of ultrapure water typically results from two main contributions: a capillary flow pushing the liquid toward the contact line from the bulk and a thermal Marangoni flow pulling the drop free surface toward the summit. Current analytical and numerical models are in good qualitative agreement with experimental observations; however, they overestimate the interfacial velocity values by two to three orders of magnitude. This discrepancy is generally ascribed to contamination of the water samples with nonsoluble surfactants; however, an experimental confirmation of this assumption has not yet been provided. In this work, we show that a small "ionic contamination" can cause a significant effect in the flow pattern inside the droplet. To provide the proof, we compare the flow in evaporating droplets of ultrapure water with commercially available bottled water of different mineralization levels. Mineral waters are bottled at natural springs, are microbiologically pure, and contain only traces of minerals (as well as traces of other possible contaminants), and therefore one would expect a slower interfacial flow as the amount of "contaminants" increase. Surprisingly, our results show that the magnitude of the interfacial flow is practically the same for mineral waters with low content of minerals as that of ultrapure water. However, for waters with larger content of minerals, the interfacial flow tends to slow down due to the presence of ionic concentration gradients. Our results show a much more complex scenario than it has been typically suspected and therefore a deeper and more comprehensive analysis of the huge differences between numerical models and experiments is necessary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevE.100.033103DOI Listing
September 2019

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Postnatal clinical phenotype of five patients with Pallister-Killian Syndrome (tetrasomy 12p): Interest of array CGH for diagnosis and review of the literature.

Mol Genet Genomic Med 2019 10 27;7(10):e00939. Epub 2019 Aug 27.

Department of Medical Genetics, Women Mothers and Children's Hospital, Lyon Hospices Civils, Lyon, France.

Background: Pallister-Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization.

Methods: Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques.

Results: Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes.

Conclusion: Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before  proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785526PMC
October 2019
-->