scholarly journals The Genetic Control of Stoichiometry Underlying Autism

2020 ◽  
Vol 43 (1) ◽  
pp. 509-533 ◽  
Author(s):  
Robert B. Darnell
Keyword(s):  
Large Scale ◽  
Biochemical Analysis ◽  
Critical Role ◽  
Gene Mutations ◽  
Loss Of Function ◽  
Case Control Studies ◽  
Neurologic Disorder ◽  
Regulatory Variants ◽  
Whole Exome ◽  
Number Variation

Autism is a common and complex neurologic disorder whose scientific underpinnings have begun to be established in the past decade. The essence of this breakthrough has been a focus on families, where genetic analyses are strongest, versus large-scale, case-control studies. Autism genetics has progressed in parallel with technology, from analyses of copy number variation to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Gene mutations causing complete loss of function account for perhaps one-third of cases, largely detected through WES. This limitation has increased interest in understanding the regulatory variants of genes that contribute in more subtle ways to the disorder. Strategies combining biochemical analysis of gene regulation, WGS analysis of the noncoding genome, and machine learning have begun to succeed. The emerging picture is that careful control of the amounts of transcription, mRNA, and proteins made by key brain genes—stoichiometry—plays a critical role in defining the clinical features of autism.

scholarly journals Association of TLR-2 Gene Polymorphisms with the Risk of Periodontitis: A Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Chao Shan ◽  
Abasijiang Aisaiti ◽  
Zhong Peng Wu ◽  
Ting Ting Wang ◽  
Jin Zhao
Keyword(s):  
Gene Polymorphisms ◽  
Large Scale ◽  
Meta Analysis ◽  
Critical Role ◽  
Case Control ◽  
Recessive Model ◽  
Immune Gene ◽  
Case Control Studies ◽  
Codominant Model ◽  
Allelic Model

Background. Periodontitis is a kind of chronic infectious disease, affecting the health of billions of people. In recent years, a number of studies have shown that multiple immune gene polymorphisms are associated with the susceptibility to periodontitis, among which TLR-2 plays a critical role in periodontitis. But most of the studies reported TLR-2 gene polymorphism and susceptibility to periodontitis are not consistent. Therefore, we included all eligible studies in our study for further meta-analysis. Methods. We used electronic databases, including CNKI, PubMed, EMBASE, and Web of Science databases, and relevant research published through June, 2020. Selecting studies involved case-control trials. For all eligibility studies, odds ratios (ORs) and 95% confidence intervals (95% CI) are provided or can be calculated from the study data. The size of the combined effect was calculated using STATA 15.0. Results. Our meta-analysis included 14 articles representing 18 case-control studies with a total of 3873 cases and 3438 control subjects. Significant association was found between periodontitis and TLR-2 rs1898830 polymorphism under the allelic model (A allele vs. G allele: p=0.014, OR=1.208, 95% CI: 1.039-1.406), recessive model (GG vs. GA+AA: p=0.028, OR=0.755, 95% CI: 0.588-0.970), and codominant model (GG VS. AA: p=0.014, OR=0.681, 95% CI: 0.501-0.925). In subgroup analysis, TLR-2 rs5743708 polymorphism was associated with periodontitis risk in Asians under an allelic model (G allele vs. A allele: p=0.017, OR=12.064, 95% CI: 1.570-92.688), dominant model (GA+AA vs.GG: p=0.016, OR=0.08, 95% CI: 0.010-0.620), and codominant model (GA VS. GG: p=0.016, OR=1.026, 95% CI: 0.821-1.282). Conclusion. The TLR-2 rs1898830, rs5743708 polymorphism may be associated with susceptibility to periodontitis. In the future, genome-wide approaches and large-scale, multiethnic case-control trials are still needed.

Mutations in CHMP4C cause dilated cardiomyopathy via dysregulation of autophagy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N.W Zhou ◽  
L Tang ◽  
Y.Y Jiang ◽  
X.J Li ◽  
W.P Zhao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Function ◽  
Critical Role ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Clinical Genetic ◽  
Whole Exome

Abstract Background Gene mutations have been implicated in DCM. However, due to the difficulty of clinical genetic diagnosis, more causal genes potentially related to DCM remain to be discovered. Methods We screened for gene mutations in more than 400 cases from families with hereditary cardiovascular disease using whole-exome sequencing. Then we validated biological functions of CHMP4C mutations in zebrafish models. To further assess the mechanism of CHMP4C mutations, we evaluated the potential signaling pathway in the cells. Results We identification of CHMP4C variants that segregated with DCM variants in four families from a total of 411 families via whole-exome sequencing. We further validate the function of CHMP4C in heart function in zebrafish models and found that over-expression of CHMP4C variants in zebrafish resulted in cardiac malformation, pericardial edema and increased heart rate, consistent with CHMP4C mutation-associated findings in DCM patients. Furthermore, we found that mutations in CHMP4C impaired autophagy and activated apoptosis in HEK293T cells, suggesting that the molecular mechanism of CHMP4C is involved in heart development. Conclusions CHMP4C is a novel candidate gene for DCM and may play a critical role in cardiac development by regulating autophagy. Funding Acknowledgement Type of funding source: None

Histology determination of lung cancers: A report on genomic profiling of lung cancer of mixing histology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8570-8570 ◽  
Author(s):  
Ming Tang ◽  
Neda Kalhor ◽  
Maheshwari Ramineni ◽  
Junya Fujimoto ◽  
Jianhua Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Critical Role ◽  
Gene Mutations ◽  
Large Cell ◽  
Small Cell ◽  
Published Data ◽  
Lung Cancers ◽  
Whole Exome ◽  
Genomic Aberrations

8570 Background: Histopathology, largely determined by morphology, plays a critical role in choosing appropriate treatment for lung cancer. The understanding of molecular determination of lung cancer histology is rudimentary. Our recently published data (Zhang, Science, 2014 and Liu, Nature Communications, 2016) have demonstrated that within the same patients with identical genetic background and identical exposure, tumor regions with different morphologic appearances may have very similar genomic profiles while tumors with the same morphology may have distinct genomic landscape. Methods: We collected 12 lung cancers of mixing histology with 2 to 4 histologic components within each tumor. In total, 26 tumor regions including 9 adenocarcinomas, 6 large-cell neuroendocrine carcinoma, 6 small cell carcinomas and 4 squamous cell carcinomas and one poorly differentiated lung carcinoma were microdissected and subjected to whole exome sequencing. Results: A substantial number of identical mutations were shared between different histologic components within the same tumor in all 12 patients. However, the proportion of shared mutations varies in different patients ranging from as little as 4% to as much as 99%. Mutation spectrum is also similar between different histologic components within the same tumors suggesting similar mutational process in place. Identical canonical cancer gene mutations including TP53, KRAS, PIK3CA, SOS1 and STK11 are generally shared between different histologic components within the same tumors. Canonical mutations in FBXW7 and MTHFR were detected in squamous component, but not small-cell component in one patient. Conclusions: Different histologic components of lung cancers of mixing histology are likely derived from the same progenitor cells, but the molecular timing of branch separation of subclones giving rise to different histologic components varies in different tumors. Although genomic aberrations may play a role in a subset of tumors, histologic features may not be determined at genomic level for most lung cancers. Gene expression and methylation analyses from these tumors are underway.

scholarly journals Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Gong ◽  
Xianru Jiao ◽  
Dan Yu ◽  
Zhixian Yang
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Ohtahara Syndrome ◽  
Whole Exome

Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

scholarly journals Postnatally Acquired Mutations Underlie the Progression of Transient Leukemia to Myeloid Leukemia of Down Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 442-442
Author(s):  
Jian Chen ◽  
Yue Li ◽  
Fouad Yousif ◽  
Sagi Abelson ◽  
Sanaz Manteghi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Digital Droplet Pcr ◽  
Whole Exome ◽  
Transient Leukemia ◽  
Droplet Pcr ◽  
A Minor

Abstract INTRODUCTION . Transient Leukemia (TL; also termed Transient Myeloproliferative disorder, TMD, and Transient Abnormal Myelopoiesis, TAM) occurs in 10-30% of newborns with Down syndrome (DS). Approx. 20% of infants with TL go on to develop acute myeloid leukemia of DS (ML-DS), typically within the first four years of life. Somatic, clone-specific mutations of GATA1 are found both in the blasts of TL and ML-DS, are concordant within the same individual and thought to function as initiating event in the development of ML-DS. In contrast, additional mutations of cohesin complex and related genes (e.g. RAD21, STAG2, CTCF), epigenetic regulators (e. g. EZH2) and signal transducers (e.g. within RAS, JAK signaling pathways) have been identified only in ML-DS blasts and are thought to cooperate with mutant GATA1 in the progression from TL to ML-DS. It is not known whether these cooperating mutations already mark a minor subclone of TL blasts at birth - allowing, at least in principle, a genetic risk stratification of TL - or are acquired postnatally during the first four years of life. OBJECTIVES . We tested the functional impact of impaired function of cohesin complex genes, CTCF and EZH2 on the progression of TL to ML-DS. We asked if mutations representing putative genetic progression events were already detectable at birth in a minor clone of TL blasts or were acquired postnatally (during the first four years of life). METHODS. The spectrum of GATA1 and cooperating mutations was determined by whole exome sequencing in fractions of TL and ML-DS blasts sorted from blood and bone marrow samples of five patients who had successively developed both disorders including one with a relapse of ML-DS. Corresponding normal T lymphocyte fractions of each patient at the stage of TL and ML-DS served as controls. Numbers of blasts harboring specific mutations were quantified by digital droplet PCR (BioRad, Inc.). Primary TL cells were transduced with lentivirus encoding shRNA (pLVX-shRNA, Clontech, Inc.) to suppress expression of cohesin complex genes, CTCF and EZH2 and intrafemurally injected into 8 week old NSG recipient mice. Engraftment in the bone marrow was assessed 8 weeks later by flow cytometry and GATA1 mutational analysis and compared to TL cells transduced with control vector. RESULTS. TL blasts harbored fewer mutations than those of ML-DS. GATA1 mutations were concordant in TL and ML-DS blasts in the same patient, consistent with development of ML-DS from subclone of TL. Knockdown of RAD21 expression in primary TL blasts, mimicking loss of function mutation of a cohesin complex gene, resulted in significantly increased engraftment of transduced cells in xenograft recipients compared to controls. This finding is consistent with RAD21 loss of function mutations playing the role of a progression event. Mutations of cohesin complex genes (SMC1A, STAG2, RAD21), NRAS and other putative cooperating mutations (with mutant GATA1) were not detectable in any sample of primary TL blasts by either whole exome sequencing or digital droplet PCR. The same result was obtained with control T lymphocytes sorted from TL samples. ML-DS blasts in one case were oligo-clonal with regard to cohesin complex gene mutations. Relapse in this patient arose from a minor clone as defined by cohesin complex gene mutations; mutations of NRAS, KNASL1 and SMC1A were present in ML-DS blasts but absent at relapse. CONCLUSIONS . Increased engraftment of TL cells with suppressed RAD21 expression is consistent with a model in which RAD21 loss of function mutations function as a progression event in the development of ML-DS. Absence of detectable cohesin complex gene mutations and other putative cooperating events in TL blasts suggests these mutations are acquired during the first four years of life and do not mark a minor clone of TL blasts present at birth. Genomic screening of TL blasts at birth therefore is unlikely to predict the risk for development of ML-DS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Exome-by-phenome-wide rare variant gene burden association with electronic health record phenotypes

2019 ◽  
Author(s):  
Joseph Park ◽  
Nathan Katz ◽  
Xinyuan Zhang ◽  
Anastasia M Lucas ◽  
Anurag Verma ◽  
...  
Keyword(s):  
Large Scale ◽  
Stop Codon ◽  
Association Studies ◽  
Whole Genome Sequencing Data ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Missense Variants ◽  
Whole Exome ◽  
Wide Scale ◽  
Electronic Health

AbstractBackgroundBy coupling large-scale DNA sequencing with electronic health records (EHR), “genome-first” approaches can enhance our understanding of the contribution of rare genetic variants to disease. Aggregating rare, loss-of-function variants in a candidate gene into a “gene burden” to test for association with EHR phenotypes can identify both known and novel clinical implications for the gene in human disease. However, this methodology has not yet been applied on both an exome-wide and phenome-wide scale, and the clinical ontologies of rare loss-of-function variants in many genes have yet to be described.MethodsWe leveraged whole exome sequencing (WES) data in participants (N=11,451) in the Penn Medicine Biobank (PMBB) to address on an exome-wide scale the association of a burden of rare loss-of-function variants in each gene with diverse EHR phenotypes using a phenome-wide association study (PheWAS) approach. For discovery, we collapsed rare (minor allele frequency (MAF) ≤ 0.1%) predicted loss-of-function (pLOF) variants (i.e. frameshift insertions/deletions, gain/loss of stop codon, or splice site disruption) per gene to perform a gene burden PheWAS. Subsequent evaluation of the significant gene burden associations was done by collapsing rare (MAF ≤ 0.1%) missense variants with Rare Exonic Variant Ensemble Learner (REVEL) scores ≥ 0.5 into corresponding yet distinct gene burdens, as well as interrogation of individual low-frequency to common (MAF > 0.1%) pLOF variants and missense variants with REVEL≥ 0.5. We replicated our findings using the UK Biobank’s (UKBB) whole exome sequence dataset (N=49,960).ResultsFrom the pLOF-based discovery phase, we identified 106 gene burdens with phenotype associations at p<10-6 from our exome-by-phenome-wide association studies. Positive-control associations included TTN (cardiomyopathy, p=7.83E-13), MYBPC3 (hypertrophic cardiomyopathy, p=3.48E-15), CFTR (cystic fibrosis, p=1.05E-15), CYP2D6 (adverse effects due to opiates/narcotics, p=1.50E-09), and BRCA2 (breast cancer, p=1.36E-07). Of the 106 genes, 12 gene-phenotype relationships were also detected by REVEL-informed missense-based gene burdens and 19 by single-variant analyses, demonstrating the robustness of these gene-phenotype relationships. Three genes showed evidence of association using both additional methods (BRCA1, CFTR, TGM6), leading to a total of 28 robust gene-phenotype associations within PMBB. Furthermore, replication studies in UKBB validated 30 of 106 gene burden associations, of which 12 demonstrated robustness in PMBB.ConclusionOur study presents 12 exome-by-phenome-wide robust gene-phenotype associations, which include three proof-of-concept associations and nine novel findings. We show the value of aggregating rare pLOF variants into gene burdens on an exome-wide scale for unbiased association with EHR phenotypes to identify novel clinical ontologies of human genes. Furthermore, we show the significance of evaluating gene burden associations through complementary, yet non-overlapping genetic association studies from the same dataset. Our results suggest that this approach applied to even larger cohorts of individuals with WES or whole-genome sequencing data linked to EHR phenotype data will yield many new insights into the relationship of genetic variation and disease phenotypes.

scholarly journals Novel Biallelic Loss-of-Function Variants in CEP290 Cause Joubert Syndrome in Two Siblings

2020 ◽  
Author(s):  
Xiang Wang ◽  
Zhu Zhang ◽  
Xueguang Zhang ◽  
Ying Shen ◽  
Hongqian Liu
Keyword(s):  
Intellectual Development ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Joubert Syndrome ◽  
Comparative Genomic ◽  
Loss Of Function ◽  
Whole Exome ◽  
Number Variation ◽  
Exon 1

Abstract BackgroundJoubert Syndrome (JS) is a rare genetic disorder, which can be defined by brainstem malformation, cerebellar vermis hypoplasia and consequent “molar tooth sign” (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here we investigated a JS case in two male siblings aged 4 and 10 years old and uncovered a novel pathogenesis through combined methods.Results The siblings shared similar features of nystagmus, delayed intellectual development. typical MTS, and abnormal morphology in fourth ventricle. Whole exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense mutation (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exon 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: qPCR, and PCR-sequencing.Conclusions In this study, we first reported a novel causative mechanism of Joubert Syndrome: a copy number variation (CNV) compounding with a point mutation in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.

Nursing professionals’ attitudes toward use of physical restraints in Styrian nursing homes Austria

Pflege ◽  
2019 ◽  
Vol 32 (1) ◽  
pp. 57-63
Author(s):  
Hannes Mayerl ◽  
Tanja Trummer ◽  
Erwin Stolz ◽  
Éva Rásky ◽  
Wolfgang Freidl
Keyword(s):  
Nursing Homes ◽  
Large Scale ◽  
Critical Role ◽  
Physical Restraint ◽  
Care Practice ◽  
Physical Restraints ◽  
Convenience Sample ◽  
Restraint Use ◽  
Positive Attitudes ◽  
Nursing Professionals

Abstract. Background: Given that nursing staff play a critical role in the decision regarding use of physical restraints, research has examined nursing professionals’ attitudes toward this practice. Aim: Since nursing professionals’ views on physical restraint use have not yet been examined in Austria to date, we aimed to explore nursing professionals’ attitudes concerning use of physical restraints in nursing homes of Styria (Austria). Method: Data were collected from a convenience sample of nursing professionals (N = 355) within 19 Styrian nursing homes, based on a cross-sectional study design. Attitudes toward the practice of restraint use were assessed by means of the Maastricht Attitude Questionnaire in the German version. Results: The overall results showed rather positive attitudes toward the use of physical restraints, yet the findings regarding the sub-dimensions of the questionnaire were mixed. Although nursing professionals tended to deny “good reasons” for using physical restraints, they evaluated the consequences of physical restraint use rather positive and considered restraint use as an appropriate health care practice. Nursing professionals’ views regarding the consequences of using specific physical restraints further showed that belts were considered as the most restricting and discomforting devices. Conclusions: Overall, Austrian nursing professionals seemed to hold more positive attitudes toward the use of physical restraints than counterparts in other Western European countries. Future nationwide large-scale surveys will be needed to confirm our findings.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

2019 ◽  
Vol 19 (9) ◽  
pp. 683-687 ◽  
Author(s):  
Tawfiq Froukh ◽  
Ammar Hawwari
Keyword(s):  
Strong Evidence ◽  
Autosomal Recessive ◽  
Eye Diseases ◽  
Initial Reaction ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Consanguineous Family ◽  
Truncated Protein ◽  
Threonine Residue ◽  
Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

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