-A rope breaks. A bell chimes. A man dies.- The kwispel: a neglected international narrative riddle genre.

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Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as \u201cwriter\u201d of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann\u2013Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein\u2013Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.</p

Innovative Genome Joint Analysis for identification of novel deep-intronic de novo pathogenic variants in KMT2A gene - WiedemannSteiner Syndrom

Heterozygous mutations in KMT2A gene are known to cause Wiedemann-Steiner Syndrome (WDSTS), a rare, autosomal dominant disease characterized by facial dysmorphism, intellectual disability, hypertrichosis cubiti, and psychomotor developmental delay. Whole genome sequencing (WGS) is a promising method to both identify pathogenic gene variants and facilitate personalized medical management

Heating system in the guesthouse

Bakalářská práce se skládá z projektu vytápění a studie. Projekt vytápění budovy penzionu se skládá z textové a výkresové části. V textové části je uveden výpočet tepelných ztrát, návrh otopných ploch, návrh dimenzí potrubí, oběhového čerpadla, expanzní nádoby a zásobníků teplé vody. Výkresová část obsahuje 6 výkresů a to rozvinutý řez, půdorysy tří nadzemních podlaží, detail technické místnosti a funkční schéma. Vše je popsáno a shrnuto v technické zprávě, která je součástí textové části. Studie se zabývá přípravou teplé vody v budově penzionu. Cílem studie je vybrat vhodný způsob přípravy teplé vody v budově penzionu a popsat jeho princip.The bachelor thesis consists of a heating project and a study. The heating project of a guest house consists of a text and drawing section. In the text part is presented the calculation of heat losses, design of heating surfaces, design of piping dimensions, circulation pump, expansion tank and hot water storage. The drawing part consists of 6 drawings, namely a developed section, three floor plans, a detail of the technical room and a functional diagram. Everything is described and summarized in the technical report that is part of the text part. The study deals with the preparation of hot water in the building of the guest house. The aim of the study is to select a suitable way of preparing hot water in the building of a guest house and describe its principle

Similarities and Differences in the Cohesinopathies of Roberts Syndrome and Cornelia de Lange Syndrome

Cohesins were first identified based on their role in chromosome segregation. The products of chromosome replication must be identified from S phase until anaphase onset in mitosis to ensure high fidelity chromosome segregation. Cohesin complexes tether together sister chromatids to maintain identity over time. More recently, cohesins were found to play numerous roles in transcription regulation and other forms of DNA metabolism, including the firing of clustered DNA replication forks, insulator function, and replication fork restart. Genetic mapping that revealed cohesin mutations are responsible for severe developmental defects spurred intense research regarding which role of cohesins was crucial to proper development. Cohesinopathies are a group of developmental disorders caused by disruption in cohesin function. Cornelia de Lange Syndrome (CdLS) and Roberts Syndrome (RBS) are two examples of cohesinopathies that exhibit a similar suite of phenotypes but are thought to arise through very different cellular mechanisms. This review investigates the similarities and differences between these two disorders to formulate a hypothesis unifying the relationship of these disorders as a possible continuum of manifestations caused by the same underlying mechanism

Innovative Whole Genome Joint Analysis – case report of early diagnosis and preventive approach to HFE Hemochromatosis

Whole Genome Joint Analysis is an innovative method to elucidate the full spectrum of genome complexities and alterations in the family members, comprehensively and unbiasedly. Once identified in the preclinical phase of the disease, causative variants can anticipate a personalized preventive approach and medical treatment

Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2

Funding Information: This work was supported by a grant from the Wiedemann-Steiner Foundation to HTB (salary coverage of TR). HTB is also supported by the Louma G. Foundation, the Icelandic Research Fund (#217988, #195835, #206806) and the Icelandic Technology Development Fund (#2010588). Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (#R01GM121459 to LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2022 Reynisdottir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Wiedemann-Steiner syndrome (WDSTS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WDSTS, we examined the spatial distribution of likely WDSTS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WDSTS variants exhibit a 61.9-fold overrepresentation within the CXXC domain–which mediates binding to unmethylated CpGs–suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted histone methylation (H3K4me1 and H3K4me3) preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 92.6% positive and 92.9% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WDSTS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, suggesting a paradigm potentially applicable to many other Mendelian disorders.Peer reviewe

Diagnosis and management in Rubinstein-Taybi syndrome:first international consensus statement

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.</p