scholarly journals The Caveolin-3 G56S sequence variant of unknown significance: Muscle biopsy findings and functional cell biological analysis

2016 ◽  
Vol 11 (1-2) ◽  
pp. 1600007 ◽  
Author(s):  
Eva Brauers ◽  
Andreas Roos ◽  
Laxmikanth Kollipara ◽  
René P. Zahedi ◽  
Alf Beckmann ◽  
...  
Keyword(s):  
Muscle Biopsy ◽  
Sequence Variant ◽  
Biological Analysis ◽  
Variant Of Unknown Significance ◽  
Unknown Significance

scholarly journals Functional testing of a human PBX3 variant in zebrafish reveals a potential modifier role in congenital heart defects

2018 ◽  
Author(s):  
Gist H. Farr ◽  
Kimia Imani ◽  
Darren Pouv ◽  
Lisa Maves
Keyword(s):  
Genome Editing ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Defects ◽  
Sequence Variant ◽  
Functional Testing ◽  
Complex Genetics ◽  
Variant Of Unknown Significance ◽  
Unknown Significance

AbstractWhole-genome and whole-exome sequencing efforts are increasingly identifying candidate genetic variants associated with human disease. However, predicting and testing the pathogenicity of a genetic variant remains challenging. Genome editing allows for the rigorous functional testing of human genetic variants in animal models. Congenital heart defects (CHDs) are a prominent example of a human disorder with complex genetics. An inherited sequence variant in the human PBX3 gene (PBX3 p.A136V) has previously been shown to be enriched in a CHD patient cohort, indicating that the PBX3 p.A136V variant could be a modifier allele for CHDs. PBX genes encode TALE (Three Amino acid Loop Extension)-class homeodomain-containing DNA-binding proteins with diverse roles in development and disease and are required for heart development in mouse and zebrafish. Here we use CRISPR-Cas9 genome editing to directly test whether this PBX gene variant acts as a genetic modifier in zebrafish heart development. We used a single-stranded oligodeoxynucleotide to precisely introduce the human PBX3 p.A136V variant in the homologous zebrafish pbx4 gene (pbx4 p.A131V). We find that zebrafish that are homozygous for pbx4 p.A131V are viable as adults. However, we show that the pbx4 p.A131V variant enhances the embryonic cardiac morphogenesis phenotype caused by loss of the known cardiac specification factor, Hand2. Our study is the first example of using precision genome editing in zebrafish to demonstrate a function for a human disease-associated single nucleotide variant of unknown significance. Our work underscores the importance of testing the roles of inherited variants, not just de novo variants, as genetic modifiers of CHDs. Our study provides a novel approach toward advancing our understanding of the complex genetics of CHDs.Summary statementOur study provides a novel example of using genome editing in zebrafish to demonstrate how a human DNA sequence variant of unknown significance may contribute to the complex genetics of congenital heart defects.

scholarly journals A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1

2021 ◽  
Author(s):  
Francisco Cammarata-Scalisi ◽  
Uta Matysiak ◽  
Colin E. Willoughby ◽  
Gunda Ruzaike ◽  
Antonio Cárdenas Tadich ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Severe Case ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Sequence Variant ◽  
Col2a1 Gene ◽  
Variant Of Unknown Significance ◽  
Spondylometaphyseal Dysplasia ◽  
Unknown Significance ◽  
Lumbar Hyperlordosis

AbstractSpondylometaphyseal dysplasia Algerian type (MIM no.: 184253) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the COL2A1 gene (MIM no.: 120140). In this case based review, we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum. Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures. The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366–13C > A in intron 21. This latter sequence variant could partially or completely disrupt the natural splice acceptor site of intron 21/exon 22 in the COL2A1 gene leading to a potential modification of the phenotypic severity.

scholarly journals From a variant of unknown significance to pathogenic: Reclassification of a large novel duplication in BRCA2 by high‐throughput sequencing

2019 ◽  
Vol 8 (9) ◽  
Author(s):  
Jana Lisa Luttikhuizen ◽  
Janin Bublitz ◽  
Stephanie Schubert ◽  
Gunnar Schmidt ◽  
Winfried Hofmann ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Variant Of Unknown Significance ◽  
Unknown Significance

P1785Whole exome sequencing unravels new genes associated with mitral valve prolapse

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Van Wijngaarden ◽  
Y L Hiemstra ◽  
T T Koopmann ◽  
C A L Ruivenkamp ◽  
E Aten ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Mitral Valve ◽  
Exome Sequencing ◽  
Mitral Valve Prolapse ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Cardiac Phenotype ◽  
Variant Of Unknown Significance ◽  
Unknown Significance ◽  
Population Databases

Abstract Background Several studies have suggested a familial clustering of mitral valve prolapse (MVP), especially for Barlow disease (BD), which is regarded as the effect of genetic or developmental errors. However, the genetic etiology of MVP, in particular BD, is largely unknown. So far only three genes have been identified: FLNA, DCHS1 and PLD1. Purpose The aim of this study was to identify genes associated with MVP using whole exome sequencing (WES). Methods Patients with MVP, who were classified as BD and/or had a positive family history for MVP, were referred for genetic counseling and WES. In total, 106 unrelated probands were included to identify potentially pathogenic variants in a set of 551 genes associated with cardiovascular development and/or diseases. The population databases Genome Aggregation and WES data from 110 parents of children with mental retardation were used as controls. Variants were analyzed using prediction programs, frequency in the population database and literature search. Variants were divided into the following categories: likely benign, variant of unknown significance or likely pathogenic. Results Thirteen percent (14/106) of the probands had a likely pathogenic variant in seven different genes: DCHS1 (1x), DSP (1x), HCN4 (2x), MYH6 (1x), TMEM67 (1x), TRPS1 (1x) and TTN (7x); the DSP, MYH6 and HCN4 variants cosegregated in affected relatives. None of the 110 parents of children with mental retardation had a likely pathogenic variant in these seven genes. In addition, 31% (33/106) of the probands harbored a variant of unknown significance in 23 different genes, including the genes DSP, FLNA, MYH6 and TTN (Fig). Remarkable, one variant of unknown significance in the FBN2 gene was shared among three unrelated probands and did not occur in population databases. Conclusion WES analysis conducted in probands with MVP using a large panel of genes associated with cardiac development and/or disease confirmed previously known causative genes (DCHS1) and expanded the cardiac phenotype of genes originally associated with cardiomyopathy (DSP, HCN4, MYH6 and TTN). This study is the first study that described the association between MVP and the genes DSP, MYH6 and TTN although the pathogenesis is still unknown. This high yield of likely pathogenic variants emphasizes the importance of genetic screening in MVP patients.

KCNJ2 Variant of Unknown Significance Reclassified as Long QT Syndrome Causing Ventricular Fibrillation

2011 ◽  
Vol 27 (6) ◽  
pp. 870.e11-870.e13 ◽  
Author(s):  
Manoj N. Obeyesekere ◽  
George J. Klein ◽  
Susan Conacher ◽  
Andrew D. Krahn
Keyword(s):  
Ventricular Fibrillation ◽  
Long Qt Syndrome ◽  
Long Qt ◽  
Variant Of Unknown Significance ◽  
Unknown Significance ◽  
Qt Syndrome

Profiling and prognostic implications of variants of unknown significance (VUS) in solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19012-e19012
Author(s):  
Meena Sadaps ◽  
Bassam N. Estfan ◽  
Wei Wei ◽  
Davendra Sohal ◽  
Megan Lynn Kruse
Keyword(s):  
Racial Disparities ◽  
Solid Tumor ◽  
Cleveland Clinic ◽  
Standard Of Care ◽  
Median Number ◽  
Rank Test ◽  
Precision Oncology ◽  
Variant Of Unknown Significance ◽  
Unknown Significance ◽  
Prognostic Implications

e19012 Background: While precision oncology is becoming increasingly integrated into standard of care for most incurable solid tumor malignancies, there is paucity of data regarding the clinical significance of VUS. In this study, we aim to evaluate whether the number of VUS is associated with overall survival (OS). We also analyze racial disparities pertaining to the number of VUS present and identify which, if any, genes possess prognostic implications. Methods: This is a retrospective review of 389 consecutive patients seen at Cleveland Clinic from 2014 to 2016 with incurable solid tumor malignancies, for whom next-generation sequencing (NGS) was ordered using Foundation One™ (Cambridge, MA). Demographics, number of VUS, genes involved, and race were summarized. OS was estimated by Kaplan-Meier and compared by log rank test. Results: Median age was 60 years, 202 (52%) patients were female, 338 (86.7%) were Caucasian, and 31 (8.0%) were African American. On NGS, 376 (97%) patients had VUS reported. The median number of VUS was 9 (range 1-116). When dichotomized at the median, the number of VUS did not affect OS. Genes most commonly implicated in reported VUS were LRP1B (88, 22.6%), MLL3 (83, 21.3%), MLL2 (73, 18.8%), ARID1B (70, 18.0%), PRKDC (60, 15.4%), PREX2 (58, 18.7%), and SPTA1 (56, 14.4%). Patients found to have a variant of unknown significance in MLL2 had worse median OS as compared to those who did not (2.61 vs 3.76 years respectively; p = 0.033). When profiled by race, Caucasians had lower numbers of VUS (p = 0.002; Table). Conclusions: We did not find a clear association between the number of VUS and OS. MLL2, a gene known to predict poor prognosis as a pathogenic variant, was seen in our study to have similarly poor prognostic implications as a variant of unknown significance. Racial disparities in genomics exist as African Americans are under-represented and have greater numbers of VUS as compared to Caucasians. Further research is warranted to elucidate these disparities. [Table: see text]

scholarly journals SAT-384 Identification of Heterozygous LRP5 Mutation and a TGFβ-1 Variant of Unknown Significance in a Patient with Hearing Loss, High Bone Mass, and Oropharyngeal Exostoses

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Cheng Cheng ◽  
James Avery ◽  
Gary Gottesman ◽  
Steven Mumm ◽  
Michael P Whyte
Keyword(s):  
Hearing Loss ◽  
Bone Mass ◽  
Family Members ◽  
Orthopedic Procedures ◽  
Appendicular Skeleton ◽  
High Bone Mass ◽  
Variant Of Unknown Significance ◽  
Cranial Nerve Palsies ◽  
Unknown Significance ◽  
High Bone

Abstract Background: Manifestations of the high bone mass (HBM) disorders not only include strong bones, but also excessive bones causing cranial nerve palsies and oropharyngeal exostoses. Due to overlap of clinical phenotype in dense bone diseases, one or more distinct genes may be involved. Up-regulation in bone formation can result from gain of function mutation of the low-density lipoprotein receptor-related protein 5 (LRP5), which mediates activation of the canonical Wnt pathway via co-binding with the frizzled protein, but may also be a consequence of activating mutations in the transforming growth factor β1 (TGFβ-1) gene that associate with stimulated osteogenesis. Clinical Case: Here we report a 41 year-old woman referred for incidentally found dense bones on screening dual-energy X-ray absorptiometry (DXA) that led to subsequent revelation of several family members sharing similar histories including inability to float in water, strong bones on skeletal surgery, and presence of palatal exostoses. Her childhood history included mandibular pain developing at age 15 years due to bony overgrowth of her lower jaw requiring multiple drilling for removal. At age 33, she manifested trigeminal neuralgia initially responsive to medical management but eventually needed microvascular decompression for unremitting pain. Preoperative brain magnetic resonance imaging (MRI) noted significant hyperostosis of the skull as well as mild narrowing of internal auditory canals, for which auditory testing showing mild mixed hearing loss in her right ear. Skeletal survey revealed diffuse thickening of axial and appendicular skeleton with characteristic endosteal hyperostosis. DXA demonstrated Z scores of +8.3 and +5.3 in the lumbar spine and total hip, respectively. Torus palatinus was also identified on exam. Mutational analysis disclosed a heterozygous LRP5 missense mutation, c.844A>G, p.Met282Val, together with a variant of unknown significance in TGFβ-1 (c.887G>A, p.Arg296Gln) possibly linked to Camurati-Engelmann disease (progressive diaphyseal dysplasia). As transmission in both conditions follows an autosomal dominant pattern, multigenerational family history was elicited from patient that her mother, who underwent knee replacement in her 80’s, was described by the surgeon as “having bones of a 30-year old man,” and that her deceased maternal grandmother possibly had “thickened” bones. Half of patient’s 18 siblings reportedly also carry features suggestive of high bone mass phenotype. Genetic testing of family members is planned. Conclusion: While HBM disorders protect against fractures, it is important to recognize that these relatively benign conditions may present with neurological and oropharyngeal complications prompting the need for their surveillance and surgical precautions during orthopedic procedures.

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