Ein einfacher dünnschichtchromatographischer Suchtest zur Erkennung von Hyperaminacidämien

Peer Reviewe

Die Blutzuckerbestimmung mit der o-Toluidin-Methode ohne Eisessig

Peer Reviewe

Evidence for 28 genetic disorders discovered by combining healthcare and research data

De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders

Organization and Information in the Fight against Crime: An Evaluation of the Integration of Police Forces in the State of Minas Gerais, Brazil *

Abstract This paper explores the experience of information sharing, coordination, and integration of actions of the Civil and Military Polices in the state of Minas Gerais, Brazil, in the context of the IGESP program. The IGESP is based on the introduction of information management systems and organizational changes akin to those associated with COMPSTAT. All the evidence presented points to a causal effect of the IGESP on crime. The most conservative estimates indicate a reduction of 24% in property crimes and 13% in personal crimes. There is also evidence that the IGESP is associated with improved police response, measured by apprehension of weapons and clearance rates. We present one of the first set of causal estimates -with a clear identification strategy -of the impact of COMPSTAT-like programs. The results suggest that the coordination and informational gains represented by the program may constitute a first-order factor in a successful policy for fighting crime

Non-Interactive Zero-Knowledge Proofs for Composite Statements

The two most common ways to design non-interactive zero-knowledge (NIZK) proofs are based on Sigma protocols and QAP-based SNARKs. The former is highly efficient for proving algebraic statements while the latter is superior for arithmetic representations. Motivated by applications such as privacy-preserving credentials and privacy-preserving audits in cryptocurrencies, we study the design of NIZKs for composite statements that compose algebraic and arithmetic statements in arbitrary ways. Specifically, we provide a framework for proving statements that consist of ANDs, ORs and function compositions of a mix of algebraic and arithmetic components. This allows us to explore the full spectrum of trade-offs between proof size, prover cost, and CRS size/generation cost. This leads to proofs for statements of the form: knowledge of $x$ such that $SHA(g^x)=y$ for some public $y$ where the prover\u27s work is 500 times fewer exponentiations compared to a QAP-based SNARK at the cost of increasing the proof size to 2404 group and field elements. In application to anonymous credentials, our techniques result in 8 times fewer exponentiations for the prover at the cost of increasing the proof size to 298 elements

Next-generation sequencing-based genome diagnostics across clinical genetics centers: Implementation choices and their effects

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care

Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation

Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8–38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0–5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance

Updatable and Universal Common Reference Strings with Applications to zk-SNARKs

By design, existing (pre-processing) zk-SNARKs embed a secret trapdoor in a relation-dependent common reference strings (CRS). The trapdoor is exploited by a (hypothetical) simulator to prove the scheme is zero knowledge, and the secret-dependent structure facilitates a linear-size CRS and linear-time prover computation. If known by a real party, however, the trapdoor can be used to subvert the security of the system. The structured CRS that makes zk-SNARKs practical also makes deploying zk-SNARKS problematic, as it is difficult to argue why the trapdoor would not be available to the entity responsible for generating the CRS. Moreover, for pre-processing zk-SNARKs a new trusted CRS needs to be computed every time the relation is changed. In this paper, we address both issues by proposing a model where a number of users can update a universal CRS. The updatable CRS model guarantees security if at least one of the users updating the CRS is honest. We provide both a negative result, by showing that zk-SNARKs with private secret-dependent polynomials in the CRS cannot be updatable, and a positive result by constructing a zk-SNARK based on a CRS consisting only of secret-dependent monomials. The CRS is of quadratic size, is updatable, and is universal in the sense that it can be specialized into one or more relation-dependent CRS of linear size with linear-time prover computation

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa

Background: Recent findings suggesting that Abelson helper integration site 1 (AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP). Methods: Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells. Results: In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base. Conclusions: This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype-phenotype correlation for AHI1 mutation associated retinal ciliopathies