A de novo ACTB gene pathogenic variant in identical twins with phenotypic variation for hydrops and jejunal atresia
Kristina SibbinPatrick YapDenis M. NyagaRaoul HellerStephen V. EvansKate StrachanSalam AlburaikyHan M. NguyenSylvie Hermann‐Le DenmatAusten R. D. GanleyJustin M. O’SullivanFrank H. Bloomfield
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Abstract:
The beta-actin gene (ACTB) encodes a ubiquitous cytoskeletal protein, essential for embryonic development in humans. De novo heterozygous missense variants in the ACTB are implicated in causing Baraitser-Winter cerebrofrontofacial syndrome (BWCFFS; MIM#243310). ACTB pathogenic variants are rarely associated with intestinal malformations. We report on a rare case of monozygotic twins presenting with proximal small bowel atresia and hydrops in one, and apple-peel bowel atresia and laryngeal dysgenesis in the other. The twin with hydrops could not be resuscitated. Intensive and surgical care was provided to the surviving twin. Rapid trio genome sequencing identified a de novo missense variant in ACTB (NM_00101.3:c.1043C>T; p.(Ser348Leu)) that guided the care plan. The identical variant subsequently was identified in the demised twin. To characterize the functional effect, the variant was recreated as a pseudoheterozygote in a haploid wild-type S. cerevisiae strain. There was an obvious growth defect of the yACT1S348L/WT pseudoheterozygote compared to a yACT1WT/WT strain when grown at 22°C but not when grown at 30°C, consistent with the yACT1 S348L variant having a functional defect that is dominant over the wild-type allele. The functional results provide supporting evidence that the Ser348Leu variant is likely to be a pathogenic variant, including being associated with intestinal malformations in BWCFFS, and can demonstrate variable expressivity within monozygotic twins.Cite
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Dravet syndrome
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Significance Pheno-RNA is a new idea/method to identify genes important for a phenotype. It involves 1) generating a phenotypic series that involves different experimental conditions to yield a measurable phenotype, 2) performing transcriptional profiling under all the conditions, and 3) correlating gene expression profiles with phenotypic strength. Using this method, we identified ∼200 genes whose expression profiles over 17 conditions show a remarkably high correlation to the level of transformation. As expected, these ∼200 genes are enriched in biological categories important for transformation. Within these categories, some genes have very high correlations with the transformation phenotype, whereas others do not. Ninety genes with high correlations have not been previously linked to cancer, suggesting heretofore unknown genes with a role in cancer.
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Abstract Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they can have drastically different effects depending on both the precise location and specific amino acid substitution of the variant. In order to better evaluate missense variation, we leveraged the exome sequencing data of 60,706 individuals from the Exome Aggregation Consortium (ExAC) dataset to identify sub-genic regions that are depleted of missense variation. We further used this depletion as part of a novel missense deleteriousness metric named MPC. We applied MPC to de novo missense variants and identified a category of de novo missense variants with the same impact on neurodevelopmental disorders as truncating mutations in intolerant genes, supporting the value of incorporating regional missense constraint in variant interpretation.
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The GJB2 gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. GJB2 pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism by which these different missense variants cause the different phenotypes is unknown. Over 2/3 of the GJB2 missense variants have yet to be functionally studied and are currently classified as variants of uncertain significance (VUS). Based on these functionally determined missense variants, we reviewed the clinical phenotypes and investigated the molecular mechanisms that affected hemichannel and gap junction functions, including connexin biosynthesis, trafficking, oligomerization into connexons, permeability, and interactions between other coexpressed connexins. We predict that all possible GJB2 missense variants will be described in the future by deep mutational scanning technology and optimizing computational models. Therefore, the mechanisms by which different missense variants cause different phenotypes will be fully elucidated.
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Abstract Approximately 15% of genetic screens for mutations in BRCA1 and BRCA2 identify Variants of Uncertain Significance (VUS). Primarily missense mutations, VUS are often difficult to interpret, leading to either uncertainty in how to properly counsel a patient or an unnecessary prophylactic surgery. Given the paucity of data for which missenses are classified as truly pathogenic, computational deleterious missense prediction (DMP) algorithms are used to predict whether a mutation is likely deleterious or neutral. Accuracy of DMPs can vary considerably and have only been calibrated on a relatively small number of missense mutations of demonstrable effect on protein function. In this study, the performance of 41 different DMPs was compared to functional data from 455 functionally characterized missense variants in BRCA1 and BRCA2. New optimized thresholds for classifying missense mutations as deleterious are presented for several existing models as well as a newly derived naïve voting method (NVM). The areas under the curve estimates for the NVM approach are between 0.889-0.922, much higher than previous methods. We estimate that the overall pathogenic potential of missense variants to be 6.8% for BRCA1 and 3.2% of BRCA2, but can be as high as 50% depending on protein location. Overall these results provide key insights into how to predict deleterious missense mutations in BRCA1 and BRCA2. Citation Format: Hart SN, Hoskin T, Shimelis H, Feng B, Lindor NM, Monteiro A, Iversen E, Goldgar DE, Suman V, Couch FJ. Optimized prediction of deleterious missense mutations in BRCA1 and BRCA2 genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-02-03.
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Objective: CENPH, centromere protein H, is one of the constitutive kinetochore proteins. High expression of CENPH has been shown in various forms of cancers; however, studies searching the effect of CENPH mutations in cancers are limited. Therefore, the aim of this study is to investigate the potential effects of the missense mutations of CENPH that have been identified in different cancers.
Materials and Methods: Missense CENPH mutations, which have been observed in cancers, were downloaded from the COSMIC v89. The effect of missense mutations was predicted by using PredictSNP1.0. The protein structure of the CENPH protein was generated with I-TASSER and missense mutations were visualized on CENPH protein with UCSF Chimera. Structural effects of selected mutations were assessed with HOPE.
Results: 34 missense mutations were observed in human cancers. Of the 34 missense mutations 18 mutations were predicted as deleterious and 16 mutations were predicted as neutral with ranging expected accuracies. Predicted missense mutations showed a scattered pattern on 3D CENPH protein. Two of the predicted deleterious missense mutations with higher expected accuracy were further analyzed and assessed according to amino acid properties.
Conclusion: This study provided a systematic analysis and evaluation of missense mutations on a CENPH protein that have been observed in different cancers.
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Objective To investigate whether there are as so ciations between missense mutation of renin gene and essential hypertension(EH). Methods There is a missense mutation in exon 9 (G1051A).A comparative study of this polymorphism in 212 hypertensive patients and 209 age -matched normotensive (NT) subjects was carried out. Results The overall distribution of G1051A was significan tly different between EH and NT.The PRA level of G/G genotype was higher than th at of A/A or G/A.Conclusion The missense mutation in exon9 may affect the enzymatical function of renin and subsequently is related with hypertension.
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