scholarly journals Truncating mutation in TANC2 in a Chinese boy associated with Lennox-Gastaut syndrome: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Tian ◽  
Zhen Shi ◽  
Chi Hou ◽  
Wenjuan Li ◽  
Xiuying Wang ◽  
...  
Keyword(s):  
Antiepileptic Drugs ◽  
Nonsense Mutation ◽  
Synapse Formation ◽  
De Novo ◽  
Association Studies ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Scaffolding Protein ◽  
Genome Wide Association Studies ◽  
Truncating Mutation

Abstract Background Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that can be caused by brain malformations or genetic mutations. Recently, genome-wide association studies have led to the identification of novel mutations associated with LGS. The TANC2 gene, encodes a synaptic scaffolding protein that interacts with other proteins at the postsynaptic density to regulate dendritic spines and excitatory synapse formation. The TANC2 gene mutations were reported in neurodevelopmental disorders and epilepsy but not in LGS ever. Case presentation Here we describe the case of a boy with LGS who presented with multiple seizure patterns, such as myoclonic, atonic, atypical absence, generalized tonic-clonic, focal seizures, and notable cognitive and motor regression. The seizures were refractory to many antiepileptic drugs. He got seizure-free with ketogenic diet combined with antiepileptic drugs. A de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene was identified by the whole-exome sequencing and confirmed by Sanger sequencing. Conclusion We described the first Chinese case with LGS associated to a de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene, which would expand the clinical spectrum related to TANC2 mutations and contribute to better understanding of genotype-phenotype relationship to guide precision medicine.

scholarly journals Genotypic and Phenotypic Characterization of Lettuce Bacterial Pathogen Xanthomonas hortorum pv. vitians Populations Collected in Quebec, Canada

Agronomy ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2386
Author(s):  
Pierre-Olivier Hébert ◽  
Martin Laforest ◽  
Dong Xu ◽  
Marie Ciotola ◽  
Mélanie Cadieux ◽  
...  
Keyword(s):  
Leaf Spot ◽  
Genome Wide Association Study ◽  
De Novo ◽  
Association Studies ◽  
Genome Wide Association ◽  
Phenotypic Characterization ◽  
Genome Wide Association Studies ◽  
Bacterial Leaf Spot ◽  
Eastern Canada ◽  
Genome Wide

Bacterial leaf spot of lettuce, caused by Xanthomonas hortorum pv. vitians, is an economically important disease worldwide. For instance, it caused around 4 million CAD in losses in only a few months during the winter of 1992 in Florida. Because only one pesticide is registered to control this disease in Canada, the development of lettuce cultivars tolerant to bacterial leaf spot remains the most promising approach to reduce the incidence and severity of the disease in lettuce fields. The lack of information about the genetic diversity of the pathogen, however, impairs breeding programs, especially when disease resistance is tested on newly developed lettuce germplasm lines. To evaluate the diversity of X. hortorum pv. vitians, a multilocus sequence analysis was performed on 694 isolates collected in Eastern Canada through the summers of 2014 to 2017 and two isolates in 1996 and 2007. All isolates tested were clustered into five phylogroups. Six pathotypes were identified following pathogenicity tests conducted in greenhouses, but when phylogroups were compared with pathotypes, no correlation could be drawn. However, in vitro production of xanthan and xanthomonadins was investigated, and isolates with higher production of xanthomonadins were generally causing less severe symptoms on the tolerant cultivar Little Gem. Whole-genome sequencing was undertaken for 95 isolates belonging to the pathotypes identified, and de novo assembly made with reads unmapped to the reference strain’s genome sequence resulted in 694 contigs ranging from 128 to 120,795 bp. Variant calling was performed prior to genome-wide association studies computed with single-nucleotide polymorphisms (SNPs), copy-number variants and gaps. Polymorphisms with significant p-values were only found on the cultivar Little Gem. Our results allowed molecular identification of isolates likely to cause bacterial leaf spot of lettuce, using two SNPs identified through genome-wide association study.

scholarly journals Cystic Fibrosis Disease Modifiers: Complex Genetics Defines the Phenotypic Diversity in a Monogenic Disease

2018 ◽  
Vol 19 (1) ◽  
pp. 201-222 ◽  
Author(s):  
Wanda K. O'Neal ◽  
Michael R. Knowles
Keyword(s):  
Cystic Fibrosis ◽  
Phenotypic Diversity ◽  
Association Studies ◽  
Gene Mutations ◽  
Monogenic Disease ◽  
Genome Wide Association Studies ◽  
Complex Genetics ◽  
Genetic Components ◽  
Significant Gene ◽  
Gene Expression Studies

In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all CFTR gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype–phenotype relationships. The non- CFTR genetic components (gene modifiers) that contribute to variation in phenotype are the focus of this review. A multifaceted approach involving candidate gene studies, genome-wide association studies, and gene expression studies has revealed significant gene modifiers for multiple CF phenotypes. The bold challenges for the future are to integrate the findings into our understanding of CF pathogenesis and to use the knowledge to develop novel therapies.

scholarly journals Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder

2019 ◽  
Author(s):  
Kunling Huang ◽  
Yuchang Wu ◽  
Junha Shin ◽  
Ye Zheng ◽  
Alireza Fotuhi Siahpirani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Association Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Transmission Disequilibrium ◽  
Fold Enrichment ◽  
Common Genetic Variants ◽  
Regulated Gene Expression

AbstractRecent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p=2.1e-7), a transcription factor (TF) mainly expressed in developmental brain. TF targets regulated by POU3F2 showed a 2.1-fold enrichment for known ASD genes (p=4.6e-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p=7.1e-5). These results provide a clear example of the connection between ASD genes affected by very rare mutations and an unlinked key regulator affected by common genetic variations.

scholarly journals YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xing-Guang Ye ◽  
Zhi-Gang Liu ◽  
Jie Wang ◽  
Jie-Min Dai ◽  
Pei-Xiu Qiao ◽  
...  
Keyword(s):  
Missense Mutation ◽  
De Novo ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Myoclonic Epilepsy ◽  
Missense Mutations ◽  
Regional Effect ◽  
Diverse Range ◽  
Mild Phenotype ◽  
Truncating Mutation

YWHAG, which encodes an adapter protein 14-3-3γ, is highly expressed in the brain and regulates a diverse range of cell signaling pathways. Previously, eight YWHAG mutations have been identified in patients with epileptic encephalopathy (EE). In this study, using trios-based whole exome sequencing, we identified two novel YWHAG mutations in two unrelated families with childhood myoclonic epilepsy and/or febrile seizures (FS). The identified mutations included a heterozygous truncating mutation (c.124C>T/p.Arg42Ter) and a de novo missense mutation (c.373A>G/p.Lys125Glu). The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment. The other affected individuals presented FS. The truncating mutation was identified in the family with six individuals of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency are relatively less pathogenic. Analysis on all missense mutations showed that nine mutations were located within 14-3-3γ binding groove and another mutation was located at residues critical for dimerization, indicating a molecular sub-regional effect. Mutation Arg132Cys, which was identified recurrently in five patients with EE, would have the strongest influence on binding affinity. 14-3-3γ dimers supports target proteins activity. Thus, a heterozygous missense mutation would lead to majority dimers being mutants; whereas a heterozygous truncating mutation would lead to only decreasing the number of wild-type dimer, being one of the explanations for phenotypical variation. This study suggests that YWHAG is potentially a candidate pathogenic gene of childhood myoclonic epilepsy and FS. The spectrum of epilepsy caused by YWHAG mutations potentially range from mild myoclonic epilepsy and FS to severe EE.

scholarly journals Parallel adaptation to higher temperatures in divergent clades of the nematodePristionchus pacificus

2016 ◽  
Author(s):  
Mark Leaver ◽  
Merve Kayhan ◽  
Angela McGaughran ◽  
Christian Roedelsperger ◽  
Anthony A. Hyman ◽  
...  
Keyword(s):  
Heat Tolerance ◽  
De Novo ◽  
Association Studies ◽  
Temperature Tolerance ◽  
Temperature Adaptation ◽  
Effect Of Temperature ◽  
Genome Wide Association Studies ◽  
Cellular Mechanisms ◽  
Ancestral Polymorphism ◽  
Evolutionary Mechanisms

AbstractStudying the effect of temperature on fertility is particularly important in the light of ongoing climate change. We need to know if organisms can adapt to higher temperatures and, if so, what are the evolutionary mechanisms behind such adaptation. Such studies have been hampered by the lack different populations of sufficient sizes with which to relate the phenotype of temperature tolerance to the underlying genotypes. Here, we examined temperature adaptation in populations of the nematodePristionchus pacificus, in which individual strains are able to successfully reproduce at 30°C. Analysis of the frequency of heat tolerant strains in different temperature zones on La Réunion supports that this trait is subject to natural selection. Reconstruction of ancestral states along the phylogeny of highly differentiatedP. pacificusclades suggests that heat tolerance evolved multiple times independently. This is further supported by genome wide association studies showing that heat tolerance is a polygenic trait and that different loci are used by individualP. pacificusclades to develop heat tolerance. More precisely, analysis of allele frequencies indicated that most genetic markers that are associated with heat tolerance are only polymorphic in individual clades. While in someP. pacificusclades, parallel evolution of heat tolerance can be explained by ancestral polymorphism or by gene flow across clades, we observe at least one clearly distinct and independent scenario where heat tolerance emerged byde novomutation. Thus, temperature tolerance evolved at least two times independently in the evolutionary history of this species. Our data suggest that studies of wild populations ofP. pacificuswill reveal distinct cellular mechanisms driving temperature adaptation.

scholarly journals Genetic Polymorphism in Peripartum Cardiomyopathy

2021 ◽  
pp. 11-5
Author(s):  
Ivana Purnama Dewi ◽  
Johanes Nugroho
Keyword(s):  
Association Studies ◽  
Case Reports ◽  
Gene Mutations ◽  
Left Ventricular ◽  
Peripartum Cardiomyopathy ◽  
Genome Wide Association Studies ◽  
Rare Type ◽  
True Incidence ◽  
Familial Dilated Cardiomyopathy ◽  
Early Case

Peripartum cardiomyopathy (PPCM) is a rare type of cardiomyopathy. PPCM is a potentially life-threatening pregnancy-associated disease that typically arises in peripartum period and is marked with left ventricular (LV) dysfunction and heart failure. The cause of PPCM remain unclear, but several mechanisms have been proposed ehich indices a potentially multi-factorial etiology. Early case reports identified overlap between familial dilated cardiomyopathy (DCM) and PPCM, although the degree of overlap is largely unknown. Many evidence supporting a contribution from gene mutations in PPCM includes genome-wide association studies, familial occurrence, variable prevalence among different regions and ethnicities, and more recent investigations of panels of genes for mutations among women with PPCM. Although the true incidence of genetic cardiomyopathy is not yet known among women with PPCM, there is substantial evidence demonstrating that genetic contribution to their condition.

scholarly journals The complex genomic basis of rapid convergent adaptation to pesticides across continents in a fungal plant pathogen

2020 ◽  
Author(s):  
Fanny E. Hartmann ◽  
Tiziana Vonlanthen ◽  
Nikhil Kumar Singh ◽  
Megan McDonald ◽  
Andrew Milgate ◽  
...  
Keyword(s):  
Selective Sweep ◽  
De Novo ◽  
Association Studies ◽  
Strong Support ◽  
Phenotypic Trait ◽  
Phenotypic Traits ◽  
Genome Wide Association Studies ◽  
Zymoseptoria Tritici ◽  
Standing Variation ◽  
Genome Wide

AbstractConvergent evolution leads to identical phenotypic traits in different species or populations. Convergence can be driven by standing variation allowing selection to favor identical alleles in parallel or the same mutations can arise independently. However, the molecular basis of such convergent adaptation remains often poorly resolved. Pesticide resistance in agricultural ecosystems is a hallmark of convergence in phenotypic traits. Here, we analyze the major fungal pathogen Zymoseptoria tritici causing serious losses on wheat and with parallel fungicide resistance emergence across continents. We sampled three population pairs each from a different continent spanning periods early and late in the application of fungicides. To identify causal loci for resistance, we combined knowledge from molecular genetics work and performed genome-wide association studies (GWAS) on a global set of isolates. We discovered yet unknown factors in azole resistance including membrane stability functions. We found strong support for the ‘hotspot’ model of resistance evolution with parallel changes in a small set of loci but additional loci showed more population-specific allele frequency changes. Genome-wide scans of selection showed that half of all known resistance loci were overlapping a selective sweep region. Hence, the application of fungicides was one of the major selective agents acting on the pathogen over the past decades. Furthermore, loci identified through GWAS showed the highest overlap with selective sweep regions underlining the importance to map phenotypic trait variation in evolving populations. Our population genomic analyses showed that both de novo mutations and gene flow likely contributed to the parallel emergence of resistance.

De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes

2021 ◽  
Vol 118 (47) ◽  
pp. e2112032118
Author(s):  
Anne-Perrine Foray ◽  
Sophie Candon ◽  
Sara Hildebrand ◽  
Cindy Marquet ◽  
Fabrice Valette ◽  
...  
Keyword(s):  
Rare Variants ◽  
De Novo ◽  
Association Studies ◽  
Nod Mice ◽  
Individual Risk ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity ◽  
Significant Difference

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

scholarly journals Two Synthetic 18-Way Outcrossed Populations of Diploid Budding Yeast with Utility for Complex Trait Dissection

Genetics ◽  
2020 ◽  
Vol 215 (2) ◽  
pp. 323-342 ◽  
Author(s):  
Robert A. Linder ◽  
Arundhati Majumder ◽  
Mahul Chakraborty ◽  
Anthony Long
Keyword(s):  
Complex Traits ◽  
De Novo ◽  
Budding Yeast ◽  
Association Studies ◽  
Haplotype Frequency ◽  
Error Rates ◽  
Genome Wide Association Studies ◽  
Link Type ◽  
Standing Variation ◽  
Median Error

Advanced-generation multiparent populations (MPPs) are a valuable tool for dissecting complex traits, having more power than genome-wide association studies to detect rare variants and higher resolution than F2 linkage mapping. To extend the advantages of MPPs in budding yeast, we describe the creation and characterization of two outbred MPPs derived from 18 genetically diverse founding strains. We carried out de novo assemblies of the genomes of the 18 founder strains, such that virtually all variation segregating between these strains is known, and represented those assemblies as Santa Cruz Genome Browser tracks. We discovered complex patterns of structural variation segregating among the founders, including a large deletion within the vacuolar ATPase VMA1, several different deletions within the osmosensor MSB2, a series of deletions and insertions at PRM7 and the adjacent BSC1, as well as copy number variation at the dehydrogenase ALD2. Resequenced haploid recombinant clones from the two MPPs have a median unrecombined block size of 66 kb, demonstrating that the population is highly recombined. We pool-sequenced the two MPPs to 3270× and 2226× coverage and demonstrated that we can accurately estimate local haplotype frequencies using pooled data. We further downsampled the pool-sequenced data to ∼20–40× and showed that local haplotype frequency estimates remained accurate, with median error rates 0.8 and 0.6% at 20× and 40×, respectively. Haplotypes frequencies are estimated much more accurately than SNP frequencies obtained directly from the same data. Deep sequencing of the two populations revealed that 10 or more founders are present at a detectable frequency for > 98% of the genome, validating the utility of this resource for the exploration of the role of standing variation in the architecture of complex traits.

scholarly journals Genetics and Management of the Patient with Orofacial Cleft

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Luciano Abreu Brito ◽  
Joanna Goes Castro Meira ◽  
Gerson Shigeru Kobayashi ◽  
Maria Rita Passos-Bueno
Keyword(s):  
Cleft Lip ◽  
Association Studies ◽  
Single Gene ◽  
Gene Mutations ◽  
Deletion Syndrome ◽  
Genome Wide Association Studies ◽  
Genetic Causes ◽  
Complex Disorder ◽  
Facial Defect ◽  
Genome Wide

Cleft lip or palate (CL/P) is a common facial defect present in 1 : 700 live births and results in substantial burden to patients. There are more than 500 CL/P syndromes described, the causes of which may be single-gene mutations, chromosomopathies, and exposure to teratogens. Part of the most prevalent syndromic CL/P has known etiology. Nonsyndromic CL/P, on the other hand, is a complex disorder, whose etiology is still poorly understood. Recent genome-wide association studies have contributed to the elucidation of the genetic causes, by raising reproducible susceptibility genetic variants; their etiopathogenic roles, however, are difficult to predict, as in the case of the chromosomal region 8q24, the most corroborated locus predisposing to nonsyndromic CL/P. Knowing the genetic causes of CL/P will directly impact the genetic counseling, by estimating precise recurrence risks, and the patient management, since the patient, followup may be partially influenced by their genetic background. This paper focuses on the genetic causes of important syndromic CL/P forms (van der Woude syndrome, 22q11 deletion syndrome, and Robin sequence-associated syndromes) and depicts the recent findings in nonsyndromic CL/P research, addressing issues in the conduct of the geneticist.

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