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Pareja, Fresia, Ryan N. Ptashkin, David N. Brown, Fatemeh Derakhshan, Pier Selenica, Edaise M. da Silva, Andrea M. Gazzo et al. "Cancer-Causative Mutations Occurring in Early Embryogenesis". Cancer Discovery 12, n.º 4 (23 de dezembro de 2021): 949–57. http://dx.doi.org/10.1158/2159-8290.cd-21-1110.
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Abstract Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers. Significance: Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring. See related commentary by Liggett and Sankaran, p. 889. This article is highlighted in the In This Issue feature, p. 873
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Shakil, Muhammad, Abida Akbar, Nazish Mahmood Aisha, Intzar Hussain, Muhammad Ikram Ullah, Muhammad Atif, Haiba Kaul et al. "Delineating Novel and Known Pathogenic Variants in TYR, OCA2 and HPS-1 Genes in Eight Oculocutaneous Albinism (OCA) Pakistani Families". Genes 13, n.º 3 (12 de março de 2022): 503. http://dx.doi.org/10.3390/genes13030503.
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Oculocutaneous albinism (OCA) is associated with a wide range of clinical presentations and has been categorized with syndromic and non-syndromic features. The most common causative genes in non-syndromic OCA are TYR and OCA2 and HSP1 is in the syndromic albinism. The objective of this study was to identify pathogenic variants in congenital OCA families from Pakistan. Eight consanguineous families were recruited, and clinical and ophthalmological examination was carried out to diagnose the disease. Whole blood was collected from the participating individuals, and genomic DNA was extracted for sequencing analysis. TruSight one-panel sequencing was carried out on one affected individual of each family, and termination Sanger sequencing was carried out to establish the co-segregation of the causative gene or genes. In silico analysis was conducted to predict the causative pathogenic variants. Two families were found to have novel genetic pathogenic variants, and six families harbored previously reported variants. One novel compound heterozygous pathogenic variant in the TYR gene, c.1002delA; p.Ala335LeufsTer20, a novel frameshift deletion pathogenic variant and c.832C>T; and p.Arg278Ter (a known pathogenic variant) were found in one family, whereas HPS1; c.437G>A; and p.Trp146Ter were detected in another family. The identification of new and previous pathogenic variants in TYR, OCA2, and HPS1 genes are causative of congenital OCA, and these findings are expanding the heterogeneity of OCA.
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Thanikachalam, Saradadevi, Elizabeth Hodapp, Ta C. Chang, Dayna Morel Swols, Filiz B. Cengiz, Shengru Guo, Mohammad F. Zafeer et al. "Spectrum of Genetic Variants Associated with Anterior Segment Dysgenesis in South Florida". Genes 11, n.º 4 (26 de março de 2020): 350. http://dx.doi.org/10.3390/genes11040350.
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Anterior segment dysgenesis (ASD) comprises a wide spectrum of developmental conditions affecting the cornea, iris, and lens, which may be associated with abnormalities of other organs. To identify disease-causing variants, we performed exome sequencing in 24 South Florida families with ASD. We identified 12 likely causative variants in 10 families (42%), including single nucleotide or small insertion–deletion variants in B3GLCT, BMP4, CYP1B1, FOXC1, FOXE3, GJA1, PXDN, and TP63, and a large copy number variant involving PAX6. Four variants were novel. Each variant was detected only in one family. Likely causative variants were detected in 1 out of 7 black and 9 out of 17 white families. In conclusion, exome sequencing for ASD allows us to identify a wide spectrum of rare DNA variants in South Florida. Further studies will explore missing variants, especially in the black communities.
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Bengani, Hemant, Detelina Grozeva, Lambert Moyon, Shipra Bhatia, Susana R. Louros, Jilly Hope, Adam Jackson et al. "Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability". PLOS ONE 16, n.º 8 (13 de agosto de 2021): e0256181. http://dx.doi.org/10.1371/journal.pone.0256181.
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Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
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Wuyun, Saina. "Causative alternation in Zuo Tradition". Language and Linguistics / 語言暨語言學 25, n.º 1 (2 de janeiro de 2024): 123–61. http://dx.doi.org/10.1075/lali.00151.wuy.
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Abstract This study examines the different variants of causative alternation in Zuo Tradition (左傳), an archaic Chinese narrative history from the Pre-Qin period. It is found that denominal verbs, unergative verbs, and “pure” unaccusative verbs participate actively in the alternation, and that the causative variant bears a complex relation with the agentive and putative variants; this causes problems for previous analyses. This paper proposes a two-step build-up of eventuality for causative alternation in archaic Chinese. Specifically, I propose that verbs in archaic Chinese are monadic and select only one argument. The merger of the verb with this argument is the realization of its eventuality conceptualized in the Lexicon; any further merger is determined by the eventuality composed by different light verbs in syntax. The uninitiated light verb is a placeholder with an empty argument. A specific light verb value is determined by the eventuality that is sent to the syntactic structure. Thus, the difference between all variants in causative alternation witnessed in Zuo Tradition lies in the different eventualities which they introduce into the syntactic configuration.
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Di Taranto, Maria Donata, e Giuliana Fortunato. "Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis". International Journal of Molecular Sciences 24, n.º 4 (6 de fevereiro de 2023): 3224. http://dx.doi.org/10.3390/ijms24043224.
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Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). Two forms of the disease are possible, heterozygous (HeFH) and homozygous (HoFH), caused by one or two pathogenic variants, respectively, in the three main genes that are responsible for the autosomal dominant disease: LDLR, APOB and PCSK9 genes. The HeFH is the most common genetic disease in humans, being the prevalence about 1:300. Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. In addition, variants in genes causing other dyslipidemias showing phenotypes overlapping with FH may mimic FH in patients without causative variants (FH-phenocopies; ABCG5, ABCG8, CYP27A1 and LIPA genes) or act as phenotype modifiers in patients with a pathogenic variant in a causative gene. The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. This review aims to report the updates on the genetic and molecular bases of FH with their implication for molecular diagnosis.
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Thongnak, Chuphong, Areerat Hnoonual, Duangkamol Tangviriyapaiboon, Suchaya Silvilairat, Apichaya Puangpetch, Ekawat Pasomsub, Wasun Chantratita, Pornprot Limprasert e Chonlaphat Sukasem. "Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder". International Journal of Genomics 2018 (2018): 1–7. http://dx.doi.org/10.1155/2018/8231547.
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Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.
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Moyon, Lambert, Camille Berthelot, Alexandra Louis, Nga Thi Thuy Nguyen e Hugues Roest Crollius. "Classification of non-coding variants with high pathogenic impact". PLOS Genetics 18, n.º 4 (29 de abril de 2022): e1010191. http://dx.doi.org/10.1371/journal.pgen.1010191.
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Whole genome sequencing is increasingly used to diagnose medical conditions of genetic origin. While both coding and non-coding DNA variants contribute to a wide range of diseases, most patients who receive a WGS-based diagnosis today harbour a protein-coding mutation. Functional interpretation and prioritization of non-coding variants represents a persistent challenge, and disease-causing non-coding variants remain largely unidentified. Depending on the disease, WGS fails to identify a candidate variant in 20–80% of patients, severely limiting the usefulness of sequencing for personalised medicine. Here we present FINSURF, a machine-learning approach to predict the functional impact of non-coding variants in regulatory regions. FINSURF outperforms state-of-the-art methods, owing in particular to optimized control variants selection during training. In addition to ranking candidate variants, FINSURF breaks down the score for each variant into contributions from individual annotations, facilitating the evaluation of their functional relevance. We applied FINSURF to a diverse set of 30 diseases with described causative non-coding mutations, and correctly identified the disease-causative non-coding variant within the ten top hits in 22 cases. FINSURF is implemented as an online server to as well as custom browser tracks, and provides a quick and efficient solution to prioritize candidate non-coding variants in realistic clinical settings.
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Thomas, Laurent F., Takaya Saito e Pål Sætrom. "Inferring causative variants in microRNA target sites". Nucleic Acids Research 39, n.º 16 (21 de junho de 2011): e109-e109. http://dx.doi.org/10.1093/nar/gkr414.
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Boudellioua, Imane, Rozaimi B. Mahamad Razali, Maxat Kulmanov, Yasmeen Hashish, Vladimir B. Bajic, Eva Goncalves-Serra, Nadia Schoenmakers, Georgios V. Gkoutos, Paul N. Schofield e Robert Hoehndorf. "Semantic prioritization of novel causative genomic variants". PLOS Computational Biology 13, n.º 4 (17 de abril de 2017): e1005500. http://dx.doi.org/10.1371/journal.pcbi.1005500.
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Abdelkader, Ehab, Oliver Brandau, Carsten Bergmann, Nuha AlSalamah, Sawsan Nowilaty e Patrik Schatz. "Novel causative variants in patients with achromatopsia". Ophthalmic Genetics 39, n.º 6 (5 de outubro de 2018): 678–83. http://dx.doi.org/10.1080/13816810.2018.1522653.
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Monasky, Michelle M., Emanuele Micaglio, Giuseppe Ciconte e Carlo Pappone. "Brugada Syndrome: Oligogenic or Mendelian Disease?" International Journal of Molecular Sciences 21, n.º 5 (1 de março de 2020): 1687. http://dx.doi.org/10.3390/ijms21051687.
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Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70–85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant’s frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype–phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.
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Shchagina, Olga, Mariya Orlova, Aisylu Murtazina, Alexandra Filatova, Mikhail Skoblov e Elena Dadali. "Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy". International Journal of Molecular Sciences 24, n.º 12 (6 de junho de 2023): 9786. http://dx.doi.org/10.3390/ijms24129786.
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The implementation of NGS methods into clinical practice allowed researchers effectively to establish the molecular cause of a disorder in cases of a genetically heterogeneous pathology. In cases of several potentially causative variants, we need additional analysis that can help in choosing a proper causative variant. In the current study, we described a family case of hereditary motor and sensory neuropathy (HMSN) type 1 (Charcot–Marie–Tooth disease). DNA analysis revealed two variants in the SH3TC2 gene (c.279G>A and c.1177+5G>A), as well as a previously described variant c.449−9C>T in the MPZ gene, in a heterozygous state. This family segregation study was incomplete because of the proband’s father's unavailability. To evaluate the variants’ pathogenicity, minigene splicing assay was carried out. This study showed no effect of the MPZ variant on splicing, but the c.1177+5G>A variant in the SH3TC2 gene leads to the retention of 122 nucleotides from intron 10 in the RNA sequence, causing a frameshift and an occurrence of a premature stop codon (NP_078853.2:p.Ala393GlyfsTer2).
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Myasnikov, Roman P., Olga V. Kulikova, Alexey N. Meshkov, Anna A. Bukaeva, Anna V. Kiseleva, Alexandra I. Ershova, Anna V. Petukhova et al. "A Splice Variant of the MYH7 Gene Is Causative in a Family with Isolated Left Ventricular Noncompaction Cardiomyopathy". Genes 13, n.º 10 (28 de setembro de 2022): 1750. http://dx.doi.org/10.3390/genes13101750.
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Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in MYH7 (MYH7tv) and associated mechanism of haploinsufficiency are usually considered not pathogenic in these disorders. However, recent large-scale studies demonstrated evidence of the significance of MYH7tv for LVNC and gave rise to an assumption that haploinsufficiency may be the causal mechanism for LVNC. In this article, we present a family with isolated LVNC and a heterozygous splice variant of the MYH7 gene, analyze possible consequences of this variant and conclude that not all variants that are predicted truncating really act through haploinsufficiency. This study can highlight the importance of a precise assessment of MYH7 splicing variants and their participation in the development of LVNC.
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Biswas, Pooja, Adda L. Villanueva, Angel Soto-Hermida, Jacque L. Duncan, Hiroko Matsui, Shyamanga Borooah, Berzhan Kurmanov et al. "Deciphering the genetic architecture and ethnographic distribution of IRD in three ethnic populations by whole genome sequence analysis". PLOS Genetics 17, n.º 10 (18 de outubro de 2021): e1009848. http://dx.doi.org/10.1371/journal.pgen.1009848.
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Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.
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Lourenco, Daniela, Shogo Tsuruta, Sungbong Jang, Breno O. Fragomeni e Ignacy Misztal. "41 Using Sequence Data to Increase Accuracy of Genomic Predictions in Livestock: Are We There Yet?" Journal of Animal Science 99, Supplement_3 (8 de outubro de 2021): 22–23. http://dx.doi.org/10.1093/jas/skab235.037.
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Abstract As sequence data is becoming available for many livestock species, there is a question on whether this information can help to boost the accuracy of genomic predictions beyond what has already been achieved with SNP chips. Several studies have been conducted by our group using simulated and real livestock populations that included from 1,000 to 100,000 animals with full or imputed sequence information. For the real datasets, the potential causative variants were identified based on genome-wide association (GWA) and were added to the current SNP chips. Additional scenarios included the use of only causative variants and the use of all sequence SNP. Genomic predictions were obtained based on single-step GBLUP (ssGBLUP), and in some cases, Bayesian regressions. Overall, in real datasets, we observed no significant increase in accuracy by using all sequence SNP, causative variants alone, or combined with SNP currently used for genomic prediction. However, an increase in accuracy of almost 100% was observed in simulated datasets when the causative variants were added to a 60k SNP panel and their simulated variances were accounted for by the prediction model. Our results show that if true causative variants are identified, together with their position and the variance explained, a boost in accuracy can be observed. This raises a question on the effectiveness of the methods and size of the datasets used to select causative variants in real livestock populations. We observed distinct GWA methods work differently depending on the data structure, and the number of genotyped animals with phenotypes. The combination of large-scale sequence and other layers of omics data (e.g., functional data) can help to identify some of the true causative variants. This could possibly promote an increase in the accuracy of genomic predictions in real populations.
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Akouchekian, Mansoureh, Mitra Hakim Shooshtari, Hamed Heidary, Fateme Zahedi Abghari e Parisa Moeinian. "The causative variants of amyloidosis in the autism". International Journal of Neuroscience 129, n.º 1 (5 de novembro de 2018): 10–15. http://dx.doi.org/10.1080/00207454.2018.1503177.
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Matczyńska, Ewa, Robert Szymańczak, Katarzyna Stradomska, Przemysław Łyszkiewicz, Maria Jędrzejowska, Karolina Kamińska, Marta Beć-Gajowniczek et al. "Whole-Exome Analysis for Polish Caucasian Patients with Retinal Dystrophies and the Creation of a Reference Genomic Database for the Polish Population". Genes 15, n.º 8 (1 de agosto de 2024): 1011. http://dx.doi.org/10.3390/genes15081011.
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We present the results of the first study of a large cohort of patients with inherited retinal dystrophies (IRD) performed for the Polish population using whole-exome sequencing (WES) in the years 2016–2019. Moreover, to facilitate such diagnostic analyses and enable future application of gene therapy and genome editing for IRD patients, a Polish genomic reference database (POLGENOM) was created based on whole-genome sequences of healthy Polish Caucasian nonagenarians and centenarians. The newly constructed database served as a control, providing a comparison for variant frequencies in the Polish population. The diagnostic yield for the selected group of IRD patients reached 64.9%. The study uncovered the most common pathogenic variants in ABCA4 and USH2A in the European population, along with several novel causative variants. A significant frequency of the ABCA4 complex haplotype p.(Leu541Pro; Ala1038Val) was observed, as well as that of the p.Gly1961Glu variant. The first VCAN causative variant NM_004385.5:c.4004-2A>G in Poland was found and described. Moreover, one of the first patients with the RPE65 causative variants was identified, and, in consequence, could receive the dedicated gene therapy. The availability of the reference POLGENOM database enabled comprehensive variant characterisation during the NGS data analysis, confirming the utility of a population-specific genomic database for enhancing diagnostic accuracy. Study findings suggest the significance of genetic testing in elder patients with unclear aetiology of eye diseases. The combined approach of NGS and the reference genomic database can improve the diagnosis, management, and future treatment of IRDs.
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Letko, Anna, Fabienne Leuthard, Vidhya Jagannathan, Daniele Corlazzoli, Kaspar Matiasek, Daniela Schweizer, Marjo K. Hytönen, Hannes Lohi, Tosso Leeb e Cord Drögemüller. "Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs". Genes 11, n.º 2 (4 de fevereiro de 2020): 163. http://dx.doi.org/10.3390/genes11020163.
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Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.
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Majeres, Leif E., Anna C. Dilger, Daniel W. Shike, Joshua C. McCann e Jonathan E. Beever. "Defining a Haplotype Encompassing the LCORL-NCAPG Locus Associated with Increased Lean Growth in Beef Cattle". Genes 15, n.º 5 (30 de abril de 2024): 576. http://dx.doi.org/10.3390/genes15050576.
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Numerous studies have shown genetic variation at the LCORL-NCAPG locus is strongly associated with growth traits in beef cattle. However, a causative molecular variant has yet to be identified. To define all possible candidate variants, 34 Charolais-sired calves were whole-genome sequenced, including 17 homozygous for a long-range haplotype associated with increased growth (QQ) and 17 homozygous for potential ancestral haplotypes for this region (qq). The Q haplotype was refined to an 814 kb region between chr6:37,199,897–38,014,080 and contained 218 variants not found in qq individuals. These variants include an insertion in an intron of NCAPG, a previously documented mutation in NCAPG (rs109570900), two coding sequence mutations in LCORL (rs109696064 and rs384548488), and 15 variants located within ATAC peaks that were predicted to affect transcription factor binding. Notably, rs384548488 is a frameshift variant likely resulting in loss of function for long isoforms of LCORL. To test the association of the coding sequence variants of LCORL with phenotype, 405 cattle from five populations were genotyped. The two variants were in complete linkage disequilibrium. Statistical analysis of the three populations that contained QQ animals revealed significant (p < 0.05) associations with genotype and birth weight, live weight, carcass weight, hip height, and average daily gain. These findings affirm the link between this locus and growth in beef cattle and describe DNA variants that define the haplotype. However, further studies will be required to define the true causative mutation.
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Niitsuma, Sou, Hiroki Kudo, Atsuo Kikuchi, Takaya Hayashi, Satoshi Kumakura, Shuhei Kobayashi, Yuko Okuyama et al. "Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome". International Immunology 32, n.º 4 (24 de dezembro de 2019): 283–92. http://dx.doi.org/10.1093/intimm/dxz081.
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Abstract Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings’ parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1β, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1β. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap−/− mice, the number of myeloid-derived suppressor cells, which require IL-1β for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.
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Bernal Barquero, Carlos Eduardo, Romina Celeste Geysels, Virginie Jacques, Gerardo Hernán Carro, Mariano Martín, Victoria Peyret, María Celeste Abregú et al. "Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect". International Journal of Molecular Sciences 23, n.º 16 (17 de agosto de 2022): 9251. http://dx.doi.org/10.3390/ijms23169251.
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Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.
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Chan, Jacqueline, Jolyon Holdstock, John Shovelton, James Reid, Graham Speight, Duarte Molha, Venu Pullabhatla et al. "Clinical and analytical validation of an 82-gene comprehensive genome-profiling panel for identifying and interpreting variants responsible for inherited retinal dystrophies". PLOS ONE 19, n.º 6 (13 de junho de 2024): e0305422. http://dx.doi.org/10.1371/journal.pone.0305422.
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Inherited retinal dystrophies comprise a clinically complex and heterogenous group of diseases characterized by visual impairment due to pathogenic variants of over 300 different genes. Accurately identifying the causative gene and associated variant is crucial for the definitive diagnosis and subsequent selection of precise treatments. Consequently, well-validated genetic tests are required in the clinical practice. Here, we report the analytical and clinical validation of a next-generation sequencing targeted gene panel, the PrismGuide IRD Panel System. This system enables comprehensive genome profiling of 82 genes related to inherited retinal dystrophies. The PrismGuide IRD Panel System demonstrated 100% (n = 43) concordance with Sanger sequencing in detecting single-nucleotide variants, small insertions, and small deletions in the target genes and also in assessing their zygosity. It also identified copy-number loss in four out of five cases. When assessing precision, we evaluated the reproducibility of variant detection with 2,160 variants in 144 replicates and found 100% agreement in terms of single-nucleotide variants (n = 1,584) and small insertions and deletions (n = 576). Furthermore, the PrismGuide IRD Panel System generated sufficient read depth for variant calls across the purine-rich and highly repetitive open-reading frame 15 region of RPGR and detected all five variants tested. These results show that the PrismGuide IRD Panel System can accurately and consistently detect single-nucleotide variants and small insertions and deletions. Thus, the PrismGuide IRD Panel System could serve as useful tool that is applicable in clinical practice for identifying the causative genes based on the detection and interpretation of variants in patients with inherited retinal dystrophies and can contribute to a precise molecular diagnosis and targeted treatments.
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Abu-Rub, Lubna I., Tara Al-Barazenji, Sumaya Abiib, Ayat S. Hammad, Alaa Abbas, Khalid Hussain e Mashael Al-Shafai. "Identification of KSR2 Variants in Pediatric Patients with Severe Early-Onset Obesity from Qatar". Genes 15, n.º 8 (23 de julho de 2024): 966. http://dx.doi.org/10.3390/genes15080966.
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The kinase suppressor of Ras 2 (KSR2) gene is associated with monogenic obesity, and loss-of-function variants in KSR2 have been identified in individuals with severe early-onset obesity. This study investigated KSR2 variants in 9 pediatric patients with severe early-onset obesity in Qatar using whole genome sequencing among a cohort of 240 individuals. We focused on KSR2 variants with a minor allele frequency (MAF) below 1% and a Combined Annotation Dependent Depletion (CADD) score above 13 to identify potential causative variants. Our analysis identified four KSR2 variants: one intronic (c.1765-8G>A) and three missense variants (c.1057G>A, c.1673G>A, and c.923T>C) in nine patients. The intronic variant c.1765-8G>A was the most frequent (seen in six individuals) and had a CADD score of 21.10, suggesting possible pathogenicity. This variant showed a significantly higher allele frequency in the Qatari population compared to the Genome Aggregation Database (gnomAD), indicating a possible founder effect. Molecular modeling of the missense variants revealed structural changes in the protein structure. The study concludes that these four KSR2 variants are associated with monogenic obesity, with an autosomal dominant inheritance pattern. The c.1765-8G>A variant’s prevalence in Qatar underscores its importance in genetic screening for severe obesity. This research advances the understanding of genetic factors in severe early-onset obesity and may inform better management strategies.
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Rasia, Maria Eugenia Mangialavori. "Stativity in the Causative Alternation? New Questions and a New Variant". Open Linguistics 5, n.º 1 (31 de dezembro de 2019): 233–59. http://dx.doi.org/10.1515/opli-2019-0014.
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AbstractThis paper discusses whether capacity to license an internal argument and eventivity are default properties of so-called change-of-state verbs.I draw attention to the claim that, in certain languages, the causative-inchoative alternation extends to a third, external-argument-only variant with stative behavior. Productivity and systematicity raise a host of problems for current generalizations on the Causative Alternation and change-of-state verbs for various reasons, starting from the long-held claim that unique arguments of change-of-state verbs are by default internal. Insofar as the causative component is independently realized in a noneventive, nonepisodic frame, this variant challenges (a) a widely agreed rule of event composition, whereby cause, if present, causally implicates process; (b) the claim that cause(r) interpretation of the external argument is a byproduct of transitivization. The present discussion: (a) brings out a crosslanguage contrast bearing on default (cause/undergoer) interpretation of unique arguments in equipollent alternations; (b) provides new empirical data supporting the stativity of the (causative) outer v head; (c) substantiates important predictions in the literature (e.g. that verbs of causation should have stative readings; that external-argument-only variants of Object-Experiencer verbs should be found); (d) captures further verb classes allowing the alternation; and (e) shows crucial contrasts with other transitive-(in/a)transitive alternations involving null/arb objects. Aspect and determination of different (a)atransitivity alternations are central throughout.
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Takao, Akinari, Tatsuro Yamaguchi, Hidetaka Eguchi, Yasushi Okazaki, Hideki Ishikawa, Kiwamu Akagi e Hideyuki Ishida. "Genetic testing of Japanese patients with serrated polyposis syndrome: A multicentric study." Journal of Clinical Oncology 42, n.º 3_suppl (20 de janeiro de 2024): 75. http://dx.doi.org/10.1200/jco.2024.42.3_suppl.75.
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75 Background: Serrated polyposis syndrome (SPS) is a rare condition associated with an increased risk of colorectal cancer. Previous studies have identified germline truncating variants of the RNF43; however, patients harboring these variants comprise a small part of those with SPS, in most of whom the causative gene remains unknown. To date, no study has described the genetic features of Japanese patients with SPS. The present study aimed to identify candidate causative genes of SPS in Japanese patients. Methods: Captures for equal to or more than 55 gene regions were performed using Agilent HaloPlex or Ion AmpliSeq technologies in SPS patients enrolled in The Study Group for Establishment of Diagnosis of Hereditary Gastrointestinal Tract Cancer Syndromes Based on a Next-Generation Sequencing Technology (SGHGCS). Whole exome sequencing of tumor tissue was performed whenever a candidate gene was identified. Results: Eleven patients (four males, seven females) were enrolled. Of these, nine had a history of colorectal cancer; four had a family history of colorectal cancer; and two had a family history of polyposis. Genetic testing identified two variants of VUS, POLD1 c.670C>T (p.R224C) and BRCA2 c.4169T>G (p.L1390W). Additionally, a nonsense variant, BUB1:c.1543G>T p.Gly515Ter was deemed likely to be pathogenic. The patient with the BUB1 variant was 47-year-old female with transverse colon cancer with more than 50 serrated polyps. She was a non-smoker. The variants detected in the transverse colon cancer did not include the canonical variants in common colorectal cancer, such as APC, KRAS or TP53 and were mostly transition substitutions (C>T). Conclusions: BUB1 was identified as a novel candidate causative gene of SPS in a patient with SPS with no smoking habit. These findings will hopefully contribute to our understanding of the genetic basis of SPS.
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Siutkina, Nadezhda P., e Svetlana V. Shustova. "COGNITIVE SCENARIO OF CAUSATIVE VERB "REIZEN" IN THE GERMAN LANGUAGE: ON THE ISSUE OF SEMANTIC POTENTIAL EXPANSION". Theoretical and Applied Linguistics, n.º 1 (2018): 84–91. http://dx.doi.org/10.22250/2410-7190_2018_4_1_84_91.
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The article focuses upon the features of the semantic potential of the emotive causative reizen. Emotive causatives are understood as causative verbs denoting interpersonal interaction resulting in modification of the emotional and psychological state of the subject. There are causatives actualizing positive and negative tone as well as axiological neutral state. The peculiarity of the verb reizen is that it can actualize all the three variants of emotional modification. The research is carried out in the aspect of functional grammar on the example of the semantic categories of causativeness, intensity and instrumentality and the interaction of these three categories. The aim of the article is to consider the cognitive scenario of the emotive causative reizen and expand its semantic potential as a result of intercategory interaction. The object of analysis is the features of the above emotive verb. The focus of our analysis is the semantic potential of this lexeme. Research methods are the following: contextual analysis, generalization and interpretation of the linguistic material...
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Naruse, Hiroya, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Masaki Tanaka, Koichiro Doi et al. "Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS". Journal of Neurology, Neurosurgery & Psychiatry 90, n.º 5 (24 de outubro de 2018): 537–42. http://dx.doi.org/10.1136/jnnp-2018-318568.
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ObjectivesTo evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series.MethodsWe conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups.ResultsWhole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants.ConclusionsA substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.
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Savelyev, V. N., I. V. Savelyeva, B. V. Babenyshev e A. N. Kulichenko. "The evolution of the pathogen and the clinical and epidemiological features of the recent cholera (el tor)". Epidemiology and Infectious Diseases 17, n.º 5 (15 de outubro de 2012): 31–35. http://dx.doi.org/10.17816/eid40707.
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In a comparative perspective studied cholera outbreak in the Caucasus due to typical toxigenic and genetically modified (hybrid) El Tor variant strains have been studied. Revealed features of the genetic structure of the genome, factors and ways of transmission of the causative agent of modern cholera El tor should be considered when improving the program of epidemiological supervision in terms of enhancing antiepidemic and prevention measures in cholera, the causative factor of which are of hybrid variants of Vibrio cholerae El tor.
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Zhang, Lujia, Ya Li, Litao Qin, Yu Wu e Bo Lei. "Autosomal Recessive Retinitis Pigmentosa Associated with Three Novel REEP6 Variants in Chinese Population". Genes 12, n.º 4 (7 de abril de 2021): 537. http://dx.doi.org/10.3390/genes12040537.
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Retinitis pigmentosa 77 is caused by mutations of REEP6 (MIM: 609346), which encodes a protein for the development of photoreceptors. Our study was to identify disease-causing variants in three Chinese families using targeted next-generation sequencing (NGS). Multiple lines of computational predictions combined with in vitro cellular experiments were applied to evaluate the pathogenicity of the newly found variants. Three novel variants in REEP6, including one missense variant, c.268G>C, one frameshift variant, c.468delC, and one splicing variant, c.598+1G>C, were found, while c.268G>C was detected in all probands. The three variants were classified as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG). REEP6 variant proteins c.268G>C and c.468delC in cultured cells destabilized the REEP6 protein and induced intracellular inclusions. Our data suggested that REEP6 c.268G>C may be a recurrent causative variant in Chinese autosomal recessive retinitis pigmentosa patients.
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Alesi, Viola, Maria Lisa Dentici, Silvia Genovese, Sara Loddo, Emanuele Bellacchio, Valeria Orlando, Silvia Di Tommaso et al. "Homozygous HESX1 and COL1A1 Gene Variants in a Boy with Growth Hormone Deficiency and Early Onset Osteoporosis". International Journal of Molecular Sciences 22, n.º 2 (13 de janeiro de 2021): 750. http://dx.doi.org/10.3390/ijms22020750.
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We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of homozygosity and two distinct homozygous variants in HESX1 (Q6H) and COL1A1 (E1361K) genes. The HESX1 variant was described as causative in a few subjects with an incompletely penetrant dominant form of combined pituitary hormone deficiency (CPHD). The COL1A1 variant is rare, and so far it has never been found in a homozygous form. Segregation analysis showed that both variants were inherited from heterozygous unaffected parents. Present results further elucidate the inheritance pattern of HESX1 variants and recommend assessing the clinical impact of variants located in C-terminal propeptide of COL1A1 gene for their potential association with rare recessive and early onset forms of osteoporosis.
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Schlingmann, Karl P., François Jouret, Kuang Shen, Anukrati Nigam, Francisco J. Arjona, Claudia Dafinger, Pascal Houillier et al. "mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy". Journal of the American Society of Nephrology 32, n.º 11 (4 de outubro de 2021): 2885–99. http://dx.doi.org/10.1681/asn.2021030333.
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BackgroundOver the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis.MethodsWe performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase).ResultsIn eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro.ConclusionsOur findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
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Suzuki, Yasuo, Kan Katayama, Ryosuke Saiki, Yosuke Hirabayashi, Tomohiro Murata, Eiji Ishikawa, Masaaki Ito e Kaoru Dohi. "Mutation Analysis of Autosomal-Dominant Polycystic Kidney Disease Patients". Genes 14, n.º 2 (9 de fevereiro de 2023): 443. http://dx.doi.org/10.3390/genes14020443.
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Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by bilateral kidney cysts that ultimately lead to end-stage kidney disease. While the major causative genes of ADPKD are PKD1 and PKD2, other genes are also thought to be involved. Fifty ADPKD patients were analyzed by exome sequencing or multiplex ligation-dependent probe amplification (MLPA), followed by long polymerase chain reaction and Sanger sequencing. Variants in PKD1 or PKD2 or GANAB were detected in 35 patients (70%). Exome sequencing identified 24, 7, and 1 variants in PKD1, PKD2, and GANAB, respectively, in 30 patients. MLPA analyses identified large deletions in PKD1 in three patients and PKD2 in two patients. We searched 90 cyst-associated genes in 15 patients who were negative by exome sequencing and MLPA analyses, and identified 17 rare variants. Four of them were considered “likely pathogenic” or “pathogenic” variants according to the American College of Medical Genetics and Genomics guidelines. Of the 11 patients without a family history, four, two, and four variants were found in PKD1, PKD2, and other genes, respectively, while no causative gene was identified in one patient. While the pathogenicity of each variant in these genes should be carefully assessed, a comprehensive genetic analysis may be useful in cases of atypical ADPKD.
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KOCAAĞA, Ayça, e Hatice Mine ÇAKMAK. "Identification of Novel Mutations in Children with Hereditary Spherocytosis by Targeted Exome Sequencing: A Single Center Experience". Medical Journal of Western Black Sea 6, n.º 3 (27 de dezembro de 2022): 296–301. http://dx.doi.org/10.29058/mjwbs.1200958.
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Aim: Hereditary spherocytosis (HS) is a prevalent cause of congenital hemolytic anemia in Northern
Europeans. It is characterized by spherocytes resulting from defects in the erythrocyte structural
membrane proteins spectrin and ankyrin. To date, more than five candidate genes, including ANK1,
SPTB, SPTA1, SLC4A1, and EPB42 have been linked to HS. Here, we aim to investigate the presence
of novel as well as known mutations in eight Turkish children with clinically suspected HS.
Material and Methods: We presented the clinical features of the patients and identified the causative
gene variants using targeted exome sequencing. Eight children who were clinically suspected of having
HS enrolled in this study. A family and medical history, clinical examination, relevant laboratory test
results, osmotic fragility test (OFT), and genetic results were evaluated.
Results: Six causative variants, including three ANK1 variants, two SPTB variants and one SLC4A1
variant were detected. All these mutations were novel variants. ANK1 and SPTB are the most common
mutant genes in children with HS.
Conclusion: This study expanded the mutation spectrum of ANK1, SPTB and SLC4A1. This is the first
study to determine the genetic and clinical characteristics of children with HS in Turkey.
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Fragomeni, B. D., D. A. L. Lourenco, Y. Masuda, A. Legarra e I. Misztal. "193 Including causative variants into single step genomic BLUP". Journal of Animal Science 95, suppl_4 (1 de agosto de 2017): 95–96. http://dx.doi.org/10.2527/asasann.2017.193.
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Wozniak, G., Y. Shen, A. Rubin, P. Neela e P. Khavari. "397 Uncovering causative, noncoding genetic variants in cutaneous diseases". Journal of Investigative Dermatology 139, n.º 5 (maio de 2019): S68. http://dx.doi.org/10.1016/j.jid.2019.03.473.
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Xrakovskij, Viktor S., e Ramazan G. Mamedshakhov. "Causative construction and its variants in Modern Standard Arabic". Orientalistica 7, n.º 1 (2024): 226–40. http://dx.doi.org/10.31696/2618-7043-2024-7-1-226-240.
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Guo, Jing, Owen J. L. Rackham, Niina Sandholm, Bing He, Anne-May Österholm, Erkka Valo, Valma Harjutsalo et al. "Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy". Journal of the American Society of Nephrology 31, n.º 2 (9 de janeiro de 2020): 309–23. http://dx.doi.org/10.1681/asn.2019030289.
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BackgroundSeveral genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated.MethodsWe carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15–37 years. We analyzed and annotated variants at genome, gene, and single-nucleotide variant levels. We then replicated the associated variants, genes, and regions in a replication cohort from the Finnish Diabetic Nephropathy study that included 3531 unrelated Finns with type 1 diabetes.ResultsWe observed protein-altering variants and an enrichment of variants in regions associated with the presence or absence of diabetic nephropathy. The replication cohort confirmed variants in both regulatory and protein-coding regions. We also observed that diabetic nephropathy–associated variants, when clustered at the gene level, are enriched in a core protein-interaction network representing proteins essential for podocyte function. These genes include protein kinases (protein kinase C isoforms ε and ι) and protein tyrosine kinase 2.ConclusionsOur comprehensive analysis of a diabetic nephropathy cohort of siblings with type 1 diabetes who were discordant for kidney disease points to variants and genes that are potentially causative or protective for diabetic nephropathy. This includes variants in two isoforms of the protein kinase C family not previously linked to diabetic nephropathy, adding support to previous hypotheses that the protein kinase C family members play a role in diabetic nephropathy and might be attractive therapeutic targets.
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Dianat, Tahereh, Dor Mohammad Kordi Tamandani, Maryam Najafi e Ali Khajeh. "Novel WDR62 and MTR Variants in a Patient With Autosomal Recessive Primary Microcephaly-2 With Polymicrogyria and Homocystinuria-Megaloblastic Anemia". Disease and Diagnosis 11, n.º 4 (1 de outubro de 2022): 142–46. http://dx.doi.org/10.34172/ddj.2022.27.
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Background: Autosomal recessive primary microcephaly-2 (MCPH2) is a rare genetic disorder with clinical and genetic heterogeneity. This study aimed to perform high-throughput whole-exome sequencing (WES) to facilitate the diagnosis of the genetic variants responsible for MCPH2 and the comorbidities. Materials and Methods: The WES was performed for a 3-year-old boy with primary microcephaly-2 and homocystinuria-megaloblastic anemia in a consanguineous family. Sequencing and variant calling was conducted by standard bioinformatics tools. Filtering was performed to prioritize novel variants. Finally, the effect of variants on the protein structure and function was assessed using web prediction tools. Results: Using WES, two novel homozygous variants and three novel homozygous variants were identified in the WDR62 and MTR genes as the causes of MCPH2 and homocystinuria-megaloblastic anemia in the affected child, respectively. These frameshift insertion variants are classified as pathogenic and affect the structure and feature of the WDR62 and MTR proteins by changing amino acid sequence and causing nonsense-mediated RNA decay (NMD). Conclusion: Magnetic resonance imaging (MRI) supported polymicrogyria and impaired cerebral cortical development in the affected child. WDR62 as a causative gene plays an essential role in cerebral cortical development, and its pathogenic disease-causing variants are considered as causing factors for MCPH2. Homocystinuria-megaloblastic anemia was a comorbidity associated with microcephaly in this patient, and its variants were confirmed by WES. Overall, performing WES is a necessary and accurate way to rapidly identify the exact causative genetic variants in MCPH2 and the homocystinuria-megaloblastic anemia and manage the disease.
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Majeres, Leif E., Anna C. Dilger, Daniel W. Shike, Joshua C. McCann e Jon E. Beever. "PSV-8 Investigation of a haplotype and eQTL analysis of the LCORL-NCAPG locus associated with increased lean growth in beef cattle". Journal of Animal Science 102, Supplement_3 (1 de setembro de 2024): 512. http://dx.doi.org/10.1093/jas/skae234.580.
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Abstract Numerous studies have shown genetic variation at the LCORL-NCAPG locus is strongly associated with growth traits in beef cattle. However, a causative molecular variant has yet to be identified. To define all possible candidate variants, Charolais-sired calves (n = 34) were whole genome sequenced including 17 homozygous for a long-range haplotype associated with increased growth (QQ), and 17 homozygous for potential ancestral haplotypes for this region (qq). The Q haplotype was refined to an 814-kb region between chr6:37,199,897-38,014,080 and contained 218 variants not found in qq individuals. These variants include an insertion in an intron of NCAPG, a previously documented mutation in NCAPG (rs109570900), two coding sequence mutations in LCORL (rs109696064 and rs384548488), and 15 variants located within ATAC peaks that were predicted to affect transcription factor binding. Notably, rs384548488 is a frameshift variant likely resulting in loss of function for long isoforms of LCORL. To test the association of the coding sequence variants of LCORL with phenotype, 405 cattle from five populations were genotyped. The two variants were in complete linkage disequilibrium. Statistical analysis of the three populations that contained QQ animals revealed significant (P < 0.05) associations with genotype and birth weight, body weight, carcass weight, hip height, and average daily gain. Additionally, an RNAseq analysis was performed using 22 of the Charolais-sired calves. This, in conjunction with the WGS data, was used to run an eQTL analysis, which revealed 256 genes whose expression were impacted by eQTL in the region (FDR < 0.05). These findings affirm the link between this locus and growth in beef cattle and describe DNA variants that define the haplotype. However, further studies will be required to define the true causative mutation.
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Arakawa, Hiroshi. "The Natural Evolution of RNA Viruses Provides Important Clues about the Origin of SARS-CoV-2 Variants". SynBio 2, n.º 3 (16 de agosto de 2024): 285–97. http://dx.doi.org/10.3390/synbio2030017.
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Despite the recent pandemic, the origin of its causative agent, SARS-CoV-2, remains controversial. This study identifies several prototype SARS-CoV-2 variants (proto-variants) that are descendants of the Wuhan variant. A thorough evaluation of the evolutionary histories of the genomes of these proto-variants reveals that most mutations in proto-variants were biased toward mutations that change the amino acid sequence. While these nonsynonymous substitutions (N mutations) were common in SARS-CoV-2 proto-variants, nucleotide changes that do not result in an amino acid change, termed synonymous substitutions (S mutations), dominate the mutations found in other RNA viruses. The N mutation bias in the SARS-CoV2 proto-variants was found in the spike gene as well as several other genes. The analysis of the ratio of N to S mutations in general RNA viruses revealed that the probability that an RNA virus spontaneously evolves a proto-variant is between 1.5 × 10−9 and 2.7 × 10−26 under natural conditions. These results suggest that SARS-CoV-2 variants did not emerge via a canonical route.
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Johnsson, Martin, e Melissa K. Jungnickel. "Evidence for and localization of proposed causative variants in cattle and pig genomes". Genetics Selection Evolution 53, n.º 1 (30 de agosto de 2021). http://dx.doi.org/10.1186/s12711-021-00662-x.
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Abstract Background This paper reviews the localization of published potential causative variants in contemporary pig and cattle reference genomes, and the evidence for their causality. In spite of the difficulties inherent to the identification of causative variants from genetic mapping and genome-wide association studies, researchers in animal genetics have proposed putative causative variants for several traits relevant to livestock breeding. Results For this review, we read the literature that supports potential causative variants in 13 genes (ABCG2, DGAT1, GHR, IGF2, MC4R, MSTN, NR6A1, PHGK1, PRKAG3, PLRL, RYR1, SYNGR2 and VRTN) in cattle and pigs, and localized them in contemporary reference genomes. We review the evidence for their causality, by aiming to separate the evidence for the locus, the proposed causative gene and the proposed causative variant, and report the bioinformatic searches and tactics needed to localize the sequence variants in the cattle or pig genome. Conclusions Taken together, there is usually good evidence for the association at the locus level, some evidence for a specific causative gene at eight of the loci, and some experimental evidence for a specific causative variant at six of the loci. We recommend that researchers who report new potential causative variants use referenced coordinate systems, show local sequence context, and submit variants to repositories.
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Inoue, Michio, Yoshihiko Saito, Takahiro Yonekawa, Megumu Ogawa, Aritoshi Iida, Ichizo Nishino e Satoru Noguchi. "Causative variant profile of collagen VI-related dystrophy in Japan". Orphanet Journal of Rare Diseases 16, n.º 1 (24 de junho de 2021). http://dx.doi.org/10.1186/s13023-021-01921-2.
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Abstract Background Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities. Methods We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis. Results Of a total of 130 families with 1–5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. Conclusions We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.
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Brabbing‐Goldstein, Dana, Lily Bazak, Noa Ruhrman‐Shahar, Gabriel Arie Lidzbarsky, Naama Orenstein, Marina Lifshiz‐Kalis, Nurit Asia‐Batzir, Yael Goldberg e Lina Basel‐Salmon. "Potentially Missed Diagnoses in Prenatal Versus Postnatal Exome Sequencing in the Lack of Informative Phenotype: Lessons Learned From a Postnatal Cohort". Prenatal Diagnosis, 5 de setembro de 2024. http://dx.doi.org/10.1002/pd.6659.
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ABSTRACTObjectiveTo investigate how many novel pathogenic (P) and likely pathogenic (LP) nonprotein‐truncating or noncanonical splicing variants would be classified as variants of unknown significance (VUS) if they were detected in fetuses without abnormalities.MethodsThe study included 156 patients with neurodevelopmental disorders diagnosed through postnatal exome sequencing. Causative P/LP nonprotein‐truncating and noncanonical splicing variants were retrospectively reclassified in cases without specific prenatal manifestations, disregarding postnatal symptoms.ResultsOf the 156 patients, 72 had a nontruncating or noncanonical splicing variant. Six patients were excluded for having more than one possible causative variant. Twelve patients had prenatal malformations known to be associated with the diagnosed disorder; therefore, variant interpretation remained unchanged. In 33 of the 54 remaining cases, the variant had been previously reported as P/LP. Reclassification of the other 21 LP/P variants revealed that 16 would have been classified as VUS if detected prenatally.ConclusionIn our cohort, ∼24% (16/66) of causative nonprotein‐truncating/noncanonical splicing variants would have been classified as VUS if sequencing had been conducted during pregnancy. The potential for false‐negative results, stemming from limitations in the phenotypic information available prenatally, should be discussed with prospective parents. The criteria for classifying and reporting variants in the prenatal setting may require adjustment.
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Seo, Yuri, Tae Young Kim, Dongju Won, Saeam Shin, Jong Rak Choi, Seung-Tae Lee, Byung Joo Lee, Hyun Taek Lim, Sueng-Han Han e Jinu Han. "Genetic spectrum and characteristics of autosomal optic neuropathy in Korean: Use of next-generation sequencing in suspected hereditary optic atrophy". Frontiers in Neurology 13 (22 de agosto de 2022). http://dx.doi.org/10.3389/fneur.2022.978532.
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AimsTo evaluate the clinical characteristics and causative genetic variants in autosomal optic atrophy diagnosed using next-generation sequencing (NGS).MethodsA cohort of 57 unrelated families affected with bilateral optic atrophy were recruited from two university-based tertiary referral hospitals from May 2016 to April 2022. Genetic variants were detected using a target enrichment panel consisting of 429 or 595 genes and known deep intronic variants associated with inherited eye diseases, exome sequencing, or genome sequencing. The results of detailed clinical examinations, disease-causing variants, and clinical diagnoses were analyzed.ResultsAmong the 57 probands, 33 (57.9%) were men, and the median age at genetic testing was 19.1 years (interquartile range, 7.6–42.5 years). We identified 22 likely causative variants in 18 families and corresponding diagnostic yields of 31.6% (95% confidence interval, 21.0–44.5%). The diagnostic rate of NGS was higher in patients with infantile or early childhood onset optic atrophy than in those with late-onset or unknown optic atrophy (18/39, 46.2% vs. 0/18, 0%, P < 0.001). Among the 22 variants, 15 were novel in our cohort. The OPA1 variants (n = 7) were found to be the major genetic causes, followed by the NR2F1 variant (n = 4). The causative variants in PTPN23, TMEM126A, NBAS, and WFS1 genes were identified in 4 probands with a recessive form of optic atrophy.ConclusionsBased on the results of diagnostic NGS for optic atrophy, the causative variant could be detected in 31.6% of patients. Our study also demonstrated that NGS is unlikely to help identify molecular causes in late-onset unexplained optic atrophy.
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Stutterd, Chloe A., Stefanie Brock, Katrien Stouffs, Miriam Fanjul-Fernandez, Paul J. Lockhart, George McGillivray, Simone Mandelstam et al. "Genetic heterogeneity of polymicrogyria: study of 123 patients using deep sequencing". Brain Communications, 26 de dezembro de 2020. http://dx.doi.org/10.1093/braincomms/fcaa221.
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Abstract Polymicrogyria is a malformation of cortical development characterized by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy, speech disturbance and motor and cognitive disability. Causes include acquired prenatal insults and inherited and de novo genetic variants. The proportion of patients with polymicrogyria and a causative germline or mosaic variant is not known. The aim of this study was to identify the monogenic causes of polymicrogyria in a heterogeneous cohort of patients reflective of specialized referral services. Patients with polymicrogyria were recruited from two clinical centres in Australia and Belgium. Patients with evidence of congenital cytomegalovirus infection or causative chromosomal copy number variants were excluded. One hundred and twenty-three patients were tested using deep sequencing gene panels including known and candidate genes for malformations of cortical development. Causative and potentially causative variants were identified and correlated with phenotypic features. Pathogenic or likely pathogenic variants were identified in 25/123 (20.3%) patients. A candidate variant was identified for an additional patient but could not be confirmed as de novo, and therefore it was classified as being of uncertain significance with high clinical relevance. Of the 22 dominant variants identified, 5 were mosaic with allele fractions less than 0.33 and the lowest allele fraction 0.09. The most common causative genes were TUBA1A and PIK3R2. The other eleven causative genes were PIK3CA, NEDD4L, COL4A1, COL4A2, GPSM2, GRIN2B, WDR62, TUBB3, TUBB2B, ACTG1 and FH. A genetic cause was more likely to be identified in the presence of an abnormal head size or additional brain malformations suggestive of a tubulinopathy, such as dysmorphic basal ganglia. A gene panel test provides greater sequencing depth and sensitivity for mosaic variants than whole exome or genome sequencing but is limited to the genes included, potentially missing variants in newly discovered genes. The diagnostic yield of 20.3% indicates that polymicrogyria may be associated with genes not yet known to be associated with brain malformations, brain-specific somatic mutations or non-genetic causes.
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Hori, Mika, Atsushi Takahashi, Kiminori Hosoda, Masatsune Ogura e Mariko Harada-Shiba. "A low-frequency APOB p.(Pro955Ser) variant contributes to the severity of/variability in familial hypercholesterolemia". Journal of Clinical Endocrinology & Metabolism, 3 de outubro de 2022. http://dx.doi.org/10.1210/clinem/dgac572.
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ABSTRACT Context Heterozygous familial hypercholesterolemia (HeFH) is caused by a rare pathogenic variant in the LDLR, APOB and PCSK9 genes. However, the causative variants in these genes have not been identified in approximately 40% of HeFH patients.Objective: Our aim was to identify novel (or additional) genes/variants that contribute to HeFH. Methods Whole-exome sequencing was performed for 215 family members from 122 families with HeFH without pathogenic variants in the LDLR or PCSK9 genes. Results We could not find novel causative FH genes/variants by family analysis. Next, we examined all APOB variants. Twenty-four nonsynonymous APOB variants were identified. The allele frequencies of the c.2863C > T:p.(Pro955Ser) variant in the HeFH probands and the general Japanese population were 0.15 and 0.034, respectively (odds ratio 4.9 [95% CI 3.4-7.1]; p = 6.9 × 10−13). The patients harboring the c.2863C > T:p.(Pro955Ser) variant accounted for 9.8% (n = 63) of unrelated patients with HeFH (n = 645). The penetrance of the c.2863C > T:p.(Pro955Ser) variant was low in the pedigree-based genetic analysis. In an in vitro assay, LDL uptake from patients with the homozygous c.2863C > T:p.(Pro955Ser) variant was 44% of the LDL uptake from control subjects, and it was similar to that of the LDL uptake from patients with the known pathogenic heterozygous p.(Arg3527Gln) variant. Conclusions The low-frequency APOB c.2863C > T:p.(Pro955Ser) variant is not an FH-causative variant, but it has a moderate effect size in HeFH. These findings suggest that the combination of the APOB c.2863C > T:p.(Pro955Ser) variant and age, environmental factors or other genetic factors contributes to the severity of or variability in the HeFH phenotype.
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Eghbali, Maryam, Kiyana Sadat Fatemi, Shadab Salehpour, Maryam Abiri, Hassan Saei, Saeed Talebi, Nasrin Alipour Olyaei, Vahid Reza Yassaee e Mohammad Hossein Modarressi. "Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi−Bickel Syndrome". Frontiers in Genetics 11 (11 de janeiro de 2021). http://dx.doi.org/10.3389/fgene.2020.601566.
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Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG’s list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG’s list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.
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Shinya, Y., T. Hiraide, M. Kataoka, M. Momoi, S. Goto, Y. Katsumata, J. Endo, M. Sano, K. Kosaki e K. Fukuda. "A novel causative gene variant, TNFRSF13B p.Gly76Ser, in patients with pulmonary arterial hypertension". European Heart Journal 41, Supplement_2 (1 de novembro de 2020). http://dx.doi.org/10.1093/ehjci/ehaa946.2310.
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Abstract Background Pulmonary artery hypertension (PAH) is a poor prognostic disease. Some causative genes were reported as the PAH-associated genes. However, the pathogenetic variants in PAH-associated genes have not been identified in majority of patients with idiopathic PAH. Purpose Our aim was to investigate the new causative gene variants associated with PAH. Methods We performed whole-exome sequencing in 272 patients with idiopathic/heritable PAH. Structural analysis simulation was performed to define how the candidate gene variant affected the structure of protein. Results We identified the heterozygous substitution change of c.226G>A (p.Gly76Ser, rs146436713) in tumor necrotic factor receptor superfamily 13B gene (TNFRSF13B) (NM_012452.2) in 6 (2.2%) patients with idiopathic/heritable PAH, although the allele frequency of this rare variant is 0% in Integrative Japanese Genome Variation Database (control population database). Two of the six cases were blood relatives, although they did not have the known causative gene variants of PAH. One of these two relatives died of right heart failure despite the combination medical therapy, and her pathological anatomy demonstrated intimal thickening and medial hypertrophy in the pulmonary arteries, formation of plexiform lesions (Heath-Edwards classification grade V). Time-lapse images from structural analysis simulation showed the instability of N-terminal in the protein, which regulates the vascular inflammation, synthesized from TNFRSF13B p.Gly76Ser variant (Figure), suggesting that p.Gly76Ser variant may be involved in the development of PAH via aberrant inflammation in pulmonary vessels. Conclusions TNFRSF13B p.Gly76Ser variant is a candidate of causative gene variant for PAH. Structural analysis of proteins Funding Acknowledgement Type of funding source: None
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Toyoda, Yu, Yusuke Kawamura, Akiyoshi Nakayama, Hirofumi Nakaoka, Toshihide Higashino, Seiko Shimizu, Hiroshi Ooyama et al. "Substantial anti-gout effect conferred by common and rare dysfunctional variants of URAT1/SLC22A12". Rheumatology, 2 de abril de 2021. http://dx.doi.org/10.1093/rheumatology/keab327.
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Abstract Objectives Gout, caused by chronic elevation of serum uric acid levels, is the commonest form of inflammatory arthritis. The causative effect of common and rare variants of ATP-binding cassette transporter G2 (ABCG2/BCRP) on gout risk has been studied, but little attention has been paid to the effect of common (rs121907892, p.W258X) and rare variants of urate transporter 1 (URAT1/SLC22A12) on gout, despite dysfunctional variants of URAT1 having been identified as pathophysiological causes of renal hypouricaemia. Methods To address this important but overlooked issue, we investigated the effects of these URAT1 variants on gout susceptibility, using targeted exon sequencing on 480 clinically defined gout cases and 480 controls of Japanese males in combination with a series of functional analyses of newly identified URAT1 variants. Results Our results show that both common and rare dysfunctional variants of URAT1 markedly decrease the risk of gout (OR 0.0338, reciprocal OR 29.6, P = 7.66 × 10−8). Interestingly, we also found that the URAT1-related protective effect on gout eclipsed the ABCG2-related causative effect (OR 2.30–3.32). Our findings reveal only one dysfunctional variant of URAT1 to have a substantial anti-gout effect, even in the presence of causative variants of ABCG2, a ‘gout gene’. Conclusion Our findings provide a better understanding of gout/hyperuricaemia and its aetiology that is highly relevant to personalized health care. The substantial anti-gout effect of common and rare variants of URAT1 identified in the present study support the genetic concept of a ‘Common Disease, Multiple Common and Rare Variant’ model.