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Introduction: Bruck syndrome is a rare autosomal recessive disease characterized by multiple joint contractures, bone fragility, and fractures. Two genes have been associated with Bruck syndrome, FKBP10 and PLOD2, though they are phenotypically indistinguishable. Case Presentation: We present a prenatally diagnosed case of Bruck syndrome in a young multiparous woman, with no notable personal, family or obstetric history. A 12-week ultrasound raised the suspicion of short long bones, subsequently confirmed at 16 weeks. In addition, bilateral fixed flexion of the elbow, wrist, and knee joints as well as talipes was observed. Chromosomal SNP microarray analysis (0.2 Mb) detected a homozygous deletion at chromosome 3, band q24, involving a part of PLOD2 to a part of PLSCR4. At mid-trimester morphology, bilateral intrauterine fractures of the humerus and femur were evident. In the late third trimester, a fetal echocardiogram noted enlargement of the right heart with severe tricuspid regurgitation in combination with pulmonary insufficiency and a restrictive arterial duct. The potential risk of premature closure of the ductus arteriosus near term led to delivery by emergency caesarean section. Conclusion: To our knowledge, this is the first case of Bruck syndrome prenatally confirmed by chromosomal microarray analysis and the second reported case with an extra-skeletal abnormality. This case highlights the importance of comprehensive fetal morphological assessment during pregnancy as diagnosis of an additional abnormality has the potential to impact both management and prognosis.

FPGA-SoCs are heterogeneous embedded computing platforms consisting of reconfigurable hardware and high-performance processing units. This combination offers flexibility and good performance for the design of embedded systems. However, allowing the sharing of resources between an FPGA and an embedded CPU enables possible attacks from one system on the other. This work demonstrates that a malicious hardware block contained inside the reconfigurable logic can manipulate the memory and peripherals of the CPU. Previous works have already considered direct memory access attacks from malicious logic on platforms containing no memory isolation mechanism. In this work, such attacks are investigated on a modern platform which contains state-of-the-art memory and peripherals isolation mechanisms. We demonstrate two attacks capable of compromising a Trusted Execution Environment based on ARM TrustZone and show a new attack capable of bypassing the secure boot configuration set by a device owner via the manipulation of Battery-Backed RAM and eFuses from malicious logic.

Hypophosphatasia (HPP) is a rare inherited disease affecting bone and dental mineralization due to loss-of-function mutations in the ALPL gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). Prenatal benign HPP (PB HPP) is a rare form of HPP characterized by in utero skeletal manifestations that progressively improve during pregnancy but often still leave symptoms after birth. Because the prenatal context limits the diagnostic tools, the main difficulty for clinicians is to distinguish PB HPP from perinatal lethal HPP, the most severe form of HPP. We previously attempted to improve genotype phenotype correlation with the help of a new classification of variants based on functional testing. Among 46 perinatal cases detected in utero or in the neonatal period for whose ALPL variants could be classified, imaging alone was thought to clearly diagnose severe lethal HPP in 35 cases, while in 11 cases, imaging abnormalities could not distinguish between perinatal lethal and BP HPP. We show here that our classification of ALPL variants may improve the ability to distinguish between perinatal lethal and PB HPP in utero.

There are thousands of distinct disease entities and concepts, each of which are known by different and sometimes contradictory names. The lack of a unified system for managing these entities poses a major challenge for both machines and humans that need to harmonize information to better predict causes and treatments for disease. The Mondo Disease Ontology is an open, community-driven ontology that integrates key medical and biomedical terminologies, supporting disease data integration to improve diagnosis, treatment, and translational research. Mondo records the sources of all data and is continually updated, making it suitable for research and clinical applications that require up-to-date disease knowledge.

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism characterized by a deficiency of the lysosomal enzyme, N‐acetylgalactosamine 6‐sulphatase (GALNS). Consequently, partially degraded GAG, chondroitin 6‐sulfate (CS) and keratan sulfate (KS), accumulate in the lysosomes of affected cells, primarily in cartilage resulting in skeletal disease. Excessive urinary excretion of these GAG is often used as the initial biochemical parameter to inform a laboratory diagnosis. Here we present the utility of a CS‐disaccharide with a non‐reducing 6‐sulfated N‐acetylgalactosamine residue (HNAc‐UA (1S))—the enzyme's substrate—for the diagnosis and biochemical monitoring of MPS IVA patients. Following implementation of this method into the diagnostic laboratory, we identified one MPS IVA patient over 3 years of MPS urine screening, with no false positive results from 2050 urines tested. Uniquely, urinary concentrations of HNAc‐UA (1S) are independent of age meaning that age‐related reference ranges are not required. Urinary HNAc‐UA (1S) was also able to identify two MPS IVA siblings who remained misdiagnosed with spondyloepiphyseal dysplasia for 5 years because of normal urinary GAG. HNAc‐UA (1S) could also be used as a biomarker for monitoring response to enzyme replacement therapy (ERT) as there was a drop in urinary concentration following the administration of ERT in all 12 patients and concentrations correlated with urinary KS (R 2 = 0.92). In conclusion, HNAc‐UA (1S) is a reliable, sensitive and specific biomarker for the diagnosis of MPS IVA and can be used to biochemically monitor the response to ERT.

Context The WNT/β-catenin pathway is central to the pathogenesis of various human diseases including those affecting bone development and tumor progression. Objective To evaluate the role of a gain-of-function variant in CTNNB1 in a child with a sclerosing bone dysplasia and an adrenocortical adenoma. Design Whole exome sequencing with corroborative biochemical analyses. Patients We recruited a child with a sclerosing bone dysplasia and an adrenocortical adenoma together with her unaffected parents. Intervention Whole exome sequencing and performance of immunoblotting and luciferase-based assays to assess the cellular consequences of a de novo variant in CTNNB1. Main Outcome Measure(s)/Result A de novo variant in CTNNB1 (c.131C>T; p.[Pro44Leu]) was identified in a patient with a sclerosing bone dysplasia and an adrenocortical adenoma. A luciferase-based transcriptional assay of WNT signaling activity verified that the activity of β-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 × 10–5). The β-catenin p.Pro44Leu variant was also associated with a decrease in phosphorylation at Ser45 and Ser33/Ser37/Thr41 in comparison to a wild-type (WT) CTNNB1 construct (P = 2.16 × 10–3, P = 9.34 × 10–8 respectively). Conclusion Increased β-catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia.

Motivation Knowledge curation from the biomedical literature is very valuable but can be a repetitive and laborious process. The paucity of user-friendly tools is one of the reasons for the lack of widespread adoption of good biomedical knowledge curation practices. Results Here, we present Ontoclick, a web browser extension that streamlines the process of annotating a text span with a relevant ontology term. We hope this tool will make biocuration more accessible to a wider audience of biomedical researchers. Availability and implementation Ontoclick is freely available under the GPL-3.0 license on the Chrome Web Store and on the Mozilla Add-Ons for Firefox Store. Source code and documentation are available at: https://github.com/azankl/Ontoclick.

Whole genome sequencing (WGS) has the potential to outperform clinical microarrays for the detection of structural variants (SV) including copy number variants (CNVs), but has been challenged by high false positive rates. Here we present ClinSV, a WGS based SV integration, annotation, prioritization, and visualization framework, which identified 99.8% of simulated pathogenic ClinVar CNVs > 10 kb and 11/11 pathogenic variants from matched microarrays. The false positive rate was low (1.5–4.5%) and reproducibility high (95–99%). In clinical practice, ClinSV identified reportable variants in 22 of 485 patients (4.7%) of which 35–63% were not detectable by current clinical microarray designs. ClinSV is available at https://github.com/KCCG/ClinSV.

System-on-Chips (SoCs) are a key enabling technology for the Internet-of-Things (IoT), a hyper-connected world where on- and inter-chip communication is ubiquitous. SoCs usually integrate cryptographic hardware cores for confidentiality and authentication services. However, these components are prone to implementation attacks. During the operation of a cryptographic core, the secret key may passively be inferred through cache observations. Access-driven attacks exploiting these observations are therefore a vital threat to SoCs operating in IoT environments. Previous works have shown the feasibility of these attacks in the SoC context. Yet, the SoC communication structure can be used to further improve access-based cache attacks. The communication attacks are not as well-understood as other micro-architectural attacks. It is important to raise the awareness of SoC designers of such a threat. To this end, we present four contributions. First, we demonstrate an improved Prime+Probe attack on four different AES-128 implementations (original transformation tables, T 0 -Only, T 2KB , and S-Box). As a novelty, this attack exploits the collisions of the bus-based SoC communication to further increase its efficiency. Second, we explore the impact of preloading on the efficiency of our communication-optimized attack. Third, we integrate three countermeasures ( shuffling , mini-tables , and Time-Division Multiple Access (TDMA) bus arbitration ) and evaluate their impact on the attack. Although shuffling and mini-tables countermeasures were proposed in previous work, their application as countermeasures against the bus-based attack was not studied before. In addition, TDMA as a countermeasure for bus-based attacks is an original contribution of this work. Fourth, we further discuss the implications of our work in the SoC design and its perspective with the new cryptographic primitives proposed in the ongoing National Institute of Standard and Technology Lightweight Cryptography competition. The results show that our improved communication-optimized attack is efficient, speeding up full key recovery by up to 400 times when compared to the traditional Prime+Probe technique. Moreover, the protection techniques are feasible and effectively mitigate the proposed improved attack.

We previously reported exome sequencing in a short-rib thoracic dystrophy (SRTD) cohort, in whom recessive mutations were identified in SRTD-associated genes in 10 of 11 cases. A heterozygous stop mutation in the known SRTD gene WDR60 was identified in the remaining case; no novel candidate gene/s were suggested by homozygous/compound heterozygous analysis. This case was thus considered unsolved. Re-analysis following an analysis pipeline update identified a homozygous mutation in C21orf2 (c.218G > C; p.Arg73Pro). This homozygous variant was previously removed at the quality control stage by the default GATK parameter “in-breeding co-efficient.” C21orf2 was recently associated with both Jeune asphyxiating thoracic dystrophy (JATD) and axial spondylometaphyseal dysplasia (axial SMD); this particular mutation was reported in homozygous and compound heterozygous state in both conditions. Our case has phenotypic features of both JATD and axial SMD; and the extent of thoracic involvement appears more severe than in other C21orf2-positive cases. Identification of a homozygous C21orf2 mutation in this case emphasizes the value of exome sequencing for simultaneously screening known genes and identifying novel genes. Additionally, it highlights the importance of re-interrogating data both as novel gene associations are identified and as analysis pipelines are refined. Finally, the severity of thoracic restriction in this case adds to the phenotypic spectrum attributable to C21orf2 mutations.

Multiprocessor System-on-Chip (MPSoC) design is based on the integration of several third-party Intellectual Property (IP) cores. Some of those IPs may include Trojans, extra hardware that can be triggered during operation time in order to perform an attack. Network-on-Chip (NoC), the communication IP of MPSoCs, can include Trojans that spy, modify and constrain the sensitive communication inside the chip. Although previous works address the malicious NoC threat, finding secure and efficient solutions is still a challenge. In this work, we propose a novel and secure network interface which implements a tunnel-based protocol that enables the secure exchange of sensitive data even in the presence of a malicious NoC. We test our technique with synthetic traffic as well as in several real application scenarios, and show that it is a secure and efficient solution.

Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 103 nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases δ and ε. The DNA polymerase α-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase α-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase α. ispartof: American Journal Of Human Genetics vol:104 issue:5 pages:957-967 ispartof: location:United States status: published

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. ispartof: Nucleic Acids Research vol:45 issue:D1 pages:D865-D876 ispartof: location:England status: published

Background Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill–Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill–Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes. Methods Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. Results A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure–a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). Conclusions The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.

Multi-Processor Systems-on-Chips (MPSoCs) are a platform for a wide variety of applications and use-cases. The high on-chip connectivity, the programming flexibility, and the reuse of IPs, however, also introduce security concerns. Problems arise when applications with different trust and protection levels share resources of the MPSoC, such as processing units, cache memories and the Network-on-Chip (NoC) communication structure. If a program gets compromised, an adversary can observe the use of these resources and infer (potentially secret) information from other applications. In this work, we explore the cache-based attack by Bogdanov et al., which infers the cache activity of a target program through timing measurements and exploits collisions that occur when the same cache location is accessed for different program inputs. We implement this differential cache-collision attack on the MPSoC Glass and introduce an optimized variant of it, the Earthquake Attack, which leverages the NoC-based communication to increase attack efficiency. Our results show that Earthquake performs well under different cache line and MPSoC configurations, illustrating that cache-collision attacks are considerable threats on MPSoCs.