scholarly journals PRRX1 Loss‐of‐Function Mutations Underlying Familial Atrial Fibrillation

2021 ◽  
Author(s):  
Xiao‐Juan Guo ◽  
Xing‐Biao Qiu ◽  
Jun Wang ◽  
Yu‐Han Guo ◽  
Chen‐Xi Yang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Target Genes ◽  
Chinese Family ◽  
Cerebral Stroke ◽  
Loss Of Function ◽  
Genetic Determinants ◽  
Bioinformatics Analyses ◽  
Genome Wide ◽  
Whole Exome ◽  
Familial Atrial Fibrillation

Background Atrial fibrillation (AF) is the most common form of clinical cardiac dysrhythmia responsible for thromboembolic cerebral stroke, congestive heart failure, and death. Aggregating evidence highlights the strong genetic basis of AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of patients, the genetic determinants underpinning AF remain elusive. Methods and Results By genome‐wide screening with polymorphic microsatellite markers and linkage analysis in a 4‐generation Chinese family affected with autosomal‐dominant AF, a novel locus for AF was mapped to chromosome 1q24.2–q25.1, a 3.20‐cM (≈4.19 Mbp) interval between markers D1S2851 and D1S218, with the greatest 2‐point logarithm of odds score of 4.8165 for the marker D1S452 at recombination fraction=0.00. Whole‐exome sequencing and bioinformatics analyses showed that within the mapping region, only the mutation in the paired related homeobox 1 ( PRRX1 ) gene, NM_022716.4:c.319C>T;(p.Gln107*), cosegregated with AF in the family. In addition, sequencing analyses of PRRX1 in another cohort of 225 unrelated patients with AF revealed a new mutation, NM_022716.4:c.437G>T; (p.Arg146Ile), in a patient. The 2 mutations were absent in 908 control subjects. Biological analyses in HeLa cells demonstrated that the 2 mutants had significantly diminished transactivation on the target genes ISL1 and SHOX2 and markedly decreased ability to bind the promoters of ISL1 and SHOX2 (2 genes causally linked to AF), although with normal intracellular distribution. Conclusions This study first indicates that PRRX1 loss‐of‐function mutations predispose to AF, which provides novel insight into the molecular pathogenesis underpinning AF, implying potential implications for precisive prophylaxis and management of AF.

scholarly journals A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yanyan Nie ◽  
Yu Mu ◽  
Jie Zheng ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mental Disorders ◽  
De Novo ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Whole Exome ◽  
De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

2019 ◽  
Vol 20 (10) ◽  
pp. 765-780 ◽  
Author(s):  
Diana Cruz ◽  
Ricardo Pinto ◽  
Margarida Freitas-Silva ◽  
José Pedro Nunes ◽  
Rui Medeiros
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Association Studies ◽  
Cardioembolic Stroke ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

2020 ◽  
Vol 105 (12) ◽  
pp. 3854-3864
Author(s):  
Jin-Fang Chai ◽  
Shih-Ling Kao ◽  
Chaolong Wang ◽  
Victor Jun-Yu Lim ◽  
Ing Wei Khor ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hba1c Level ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Specific Reference ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P &lt; 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

scholarly journals Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

2018 ◽  
Author(s):  
Satish K Nandakumar ◽  
Sean K McFarland ◽  
Laura Marlene Mateyka ◽  
Caleb A Lareau ◽  
Jacob C Ulirsch ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Target Genes ◽  
Association Studies ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Causal Variants ◽  
Genomic Regions

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding genomic regions and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in relevant biological pathways, allowing regulators of human erythropoiesis and blood disease modifiers to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.

ISL1 loss-of-function variation causes familial atrial fibrillation

2020 ◽  
Vol 63 (11) ◽  
pp. 104029
Author(s):  
Shao-Hui Wu ◽  
Xin-Hua Wang ◽  
Ying-Jia Xu ◽  
Jia-Ning Gu ◽  
Chen-Xi Yang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Loss Of Function ◽  
Familial Atrial Fibrillation

Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Qi Qiao ◽  
Cui-Mei Zhao ◽  
Chen-Xi Yang ◽  
Jia-Ning Gu ◽  
Yu-Han Guo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dilated Cardiomyopathy ◽  
Sanger Sequencing ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Functional Characterization ◽  
Luciferase Assay ◽  
Chinese Family ◽  
Sequencing Analysis ◽  
Loss Of Function

AbstractObjectivesDilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive.MethodsWhole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system.ResultsA heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM.ConclusionsThe findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.

scholarly journals Paupar LncRNA Promotes KAP1 Dependent Chromatin Changes And Regulates Subventricular Zone Neurogenesis

2017 ◽  
Author(s):  
Ioanna Pavlaki ◽  
Farah Alammari ◽  
Bin Sun ◽  
Neil Clark ◽  
Tamara Sirey ◽  
...  
Keyword(s):  
Subventricular Zone ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Neuroblastoma Cell ◽  
Regulatory Protein ◽  
Regulatory Elements ◽  
Loss Of Function ◽  
Transcriptional Regulatory Elements ◽  
Genome Wide

ABSTRACTMany long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their in vivo roles and molecular mechanisms of action remain poorly understood. Paupar, a CNS expressed lncRNA, controls neuroblastoma cell growth by binding and modulating the activity of genome-wide transcriptional regulatory elements. We show here that Paupar transcript directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation. Paupar promotes KAP1 chromatin occupancy and H3K9me3 deposition at a subset of distal targets, through formation of a DNA binding ribonucleoprotein complex containing Paupar, KAP1 and the PAX6 transcription factor. Paupar-KAP1 genome-wide co-occupancy reveals a 4-fold enrichment of overlap between Paupar and KAP1 bound sequences. Furthermore, both Paupar and Kap1 loss of function in vivo accelerates lineage progression in the mouse postnatal subventricular zone (SVZ) stem cell niche and disrupts olfactory bulb neurogenesis. These observations provide important conceptual insights into the trans-acting modes of lncRNA-mediated epigenetic regulation, the mechanisms of KAP1 genomic recruitment and identify Paupar and Kap1 as regulators of SVZ neurogenesis.

scholarly journals Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei

2019 ◽  
Author(s):  
Mei Sim Lung ◽  
Catherine A. Mitchell ◽  
Maria A. Doyle ◽  
Andrew C. Lynch ◽  
Kylie L. Gorringe ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Pseudomyxoma Peritonei ◽  
Loss Of Function ◽  
Germline Variants ◽  
Missense Variants ◽  
Genome Wide ◽  
Whole Exome ◽  
Predisposing Genes ◽  
Mucinous Tumours

Abstract Background Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. Methods Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH. Results Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes ( EXOG , RANBP2, RANBP6 and TNFRSF1B ) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified. Conclusion Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.

scholarly journals Identifying Possible Candidate Factors Influencing the Penetrance of Heterozygous NFKB1 Loss of Function Mutations By Whole Exome Sequencing

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3706-3706
Author(s):  
Cyrill Schipp ◽  
Arndt Borkhardt ◽  
Polina Stepensky ◽  
Ute Fischer
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Bioinformatics Analyses ◽  
Factors Influencing ◽  
Whole Exome

Abstract Introduction The NFκB signaling pathway is a master regulator of immune and inflammatory responses. Recently we and other groups reported heterozygous NFKB1 loss-of-function mutations in patients with combined variable immunodeficiency (CVID) characterized by recurrent infections, autoimmunity and immunoglobulin deficiency. Pedigree analysis revealed incomplete penetrance of the disease causing mutation in 5 of the 6 analyzed families. While patients showed a severe phenotype including hypogammaglobulinemia, chronic infections and cytopenias, other carriers of the same mutation were unaffected except for slightly perturbed immunoglobulin levels indicating the existence of other factors influencing the penetrance of these mutations. Methods To identify genetic factors associated with complete penetrance of dominant NFKB1 mutations, whole exome sequencing was carried out using DNA extracted from blood samples derived from two patients and their families. Sequencing data of two patients and X unaffected carriers of the same NFKB1 mutations (p.R157X and p.I47fsX2) were then screened in silico for single nucleotide variations, small insertions and deletions present in modulators of immune responses in general and the NFκB pathway in particular, employing lists generated based on publicly available data on gene interactions (including e.g. data of the KEGG, and STRING databases). Results We detected no deleterious mutations in known modifier genes such as IL10, IL1B, IL6, CCR5, CCL5, RANTES, TGFB1 and others. But strikingly both patients harbored two polymorphisms (g.797C>A, Gly54Asp, Gly57Glu) in the Mannose Binding Lectin 2 (MBL2) gene that were previously reported as disease causing mutations in patients with primary immunodeficiency. These polymorphisms lead to reduced MBL2 expression and are linked with high susceptibility to infections. We hypothesize that low MBL2 expression in an NFKB1 haploinsufficient background may promote disease penetrance or increase the predisposition to infections. Conclusion Our combined next-generation sequencing and bioinformatics analyses approach identified MBL2 as an interesting candidate factor whose deficient expression may influence the penetrance of NFKB1 loss-of-function mutations. Further analysis of greater cohorts is needed to reinforce the role of MBL2 in the pathogenesis of NFKB1 haploinsufficiency. Disclosures No relevant conflicts of interest to declare.

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