scholarly journals PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease

2021 ◽  
Author(s):  
Manon H.C.A Peeters ◽  
Mubeen Khan ◽  
Anoek A.M.B Rooijakkers ◽  
Timo Mulders ◽  
Lonneke Haer-Wigman ◽  
...  
Keyword(s):  
Retinal Disease ◽  
Variants Of Unknown Significance ◽  
Novel Variants ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Variation Database ◽  
The Many ◽  
Source Variation ◽  
Additional Index

Mutations in PRPH2, encoding peripherin-2, are associated with the development of a wide variety of inherited retinal diseases (IRDs). To determine the causality of the many PRPH2 variants that have been discovered over the last decades, we surveyed all published PRPH2 variants up to July 2020, describing 720 index patients that in total carried 245 unique variants. In addition, we identified seven novel PRPH2 variants in eight additional index patients. The pathogenicity of all variants was determined using the ACMG guidelines. With this, 107 variants were classified as pathogenic, 92 as likely pathogenic, one as benign, and two as likely benign. The remaining 50 variants were classified as variants of uncertain significance. Interestingly, of the in total 252 PRPH2 variants, more than half (n=137) were missense variants. All variants were uploaded into the Leiden Open source Variation Database. Our study underscores the need of experimental assays for variants of unknown significance to improve pathogenicity classification, which is needed to better understand genotype-phenotype correlations, and in the long-term, hopefully also support the development of therapeutic strategies for patients with PRPH2-associated IRD.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Novel variants of unknown significance in the PMS2 gene identified in patients with hereditary colon cancer

2019 ◽  
Vol Volume 11 ◽  
pp. 6719-6725 ◽  
Author(s):  
Raffaella Liccardo ◽  
Carlo Della Ragione ◽  
Nunzio Mitilini ◽  
Marina De Rosa ◽  
Paola Izzo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Hereditary Colon Cancer ◽  
Variants Of Unknown Significance ◽  
Novel Variants ◽  
Unknown Significance ◽  
Em Gene

scholarly journals Interpreting Osteogenesis Imperfecta Variants of Uncertain Significance in the Context of Physical Abuse: A Case Series

2018 ◽  
Vol 08 (02) ◽  
pp. 063-068
Author(s):  
Jennifer Canter ◽  
Vinod Rao ◽  
Vincent Palusci ◽  
David Kronn ◽  
Michal Manaster ◽  
...  
Keyword(s):  
Child Abuse ◽  
Osteogenesis Imperfecta ◽  
Physical Abuse ◽  
Clinical Significance ◽  
Case Series ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Potential Abuse ◽  
Uncertain Significance

AbstractUnexplained childhood fracture(s) warrant consideration of physical abuse and osteogenesis imperfecta (OI). Genetic OI testing may identify “variants of unknown significance (VUS).” Interpretation of VUS in context of potential abuse may have protective, criminal, and medical impacts. This case series explores practices regarding clinicians' interpretation of VUS during child abuse evaluations. Variability was noted regarding factors considered for interpreting clinical significance. Based on these cases, recommendations for careful and thorough evaluation are detailed, including proposed use of a limited follow-up skeletal survey in 3 months, as a consideration to assess healing of prior fractures and to look for any additional injuries.

scholarly journals The Changing Face of Adrenoleukodystrophy

2020 ◽  
Vol 41 (4) ◽  
pp. 577-593 ◽  
Author(s):  
Jia Zhu ◽  
Florian Eichler ◽  
Alessandra Biffi ◽  
Christine N Duncan ◽  
David A Williams ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Adrenal Insufficiency ◽  
Hematopoietic Stem ◽  
Neurological Outcomes ◽  
Variants Of Unknown Significance ◽  
Disease Modifying Therapy ◽  
Novel Variants ◽  
Unknown Significance ◽  
Therapy Clinical Trial ◽  
Timely Treatment

Abstract Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 – 17, 2020)

scholarly journals Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance

2021 ◽  
Vol 10 (9) ◽  
pp. 1806
Author(s):  
Mercedes Iglesias ◽  
Tomas Ripoll-Vera ◽  
Consuelo Perez-Luengo ◽  
Ana Belen García ◽  
Susana Moyano ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Ventricular Hypertrophy ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Molecular Autopsy ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Frequent Variant

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.

scholarly journals Characterizing variants of unknown significance in rhodopsin: a functional genomics approach

2019 ◽  
Author(s):  
Aliete Wan ◽  
Emily Place ◽  
Eric A. Pierce ◽  
Jason Comander
Keyword(s):  
Human Genetics ◽  
Functional Characterization ◽  
Diagnostic Testing ◽  
Retinal Disease ◽  
Surface Expression ◽  
Disease Genes ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Next Generation Sequencing Ngs ◽  
High Degree

AbstractCharacterizing the pathogenicity of DNA sequence variants of unknown significance (VUS) is a major bottleneck in human genetics, and is increasingly important in determining which patients with inherited retinal diseases could benefit from gene therapy. A library of 210 rhodopsin (RHO) variants from literature and in-house genetic diagnostic testing was created to efficiently detect pathogenic RHO variants that fail to express on the cell surface. This study, while focused on RHO, demonstrates a streamlined, generalizable method for detecting pathogenic VUS. A relatively simple next generation sequencing (NGS)-based readout was developed so that a flow cytometry-based assay could be performed simultaneously on all variants in a pooled format, without the need for barcodes or viral transduction. The resulting dataset characterized surface expression of every RHO library variant with a high degree of reproducibility (Z’=0.94, R2=0.92-0.95), recategorizing 37 variants. For example, three retinitis pigmentosa pedigrees were solved by identifying VUS which showed low expression levels (G18D, G101V, P180T). Results were validated across multiple assays and correlated with clinical disease severity. This study presents a parallelized, higher-throughput cell-based assay for the functional characterization of VUS in rhodopsin, and can be applied more broadly to other inherited retinal disease genes and other disorders.

Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult AML patients

Blood ◽  
2021 ◽  
Author(s):  
Fei Yang ◽  
Nicola Long ◽  
Tauangtham Anekpuritanang ◽  
Daniel Bottomly ◽  
Jonathan C. Savage ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Sequencing Data ◽  
Germline Variants ◽  
Variant Of Uncertain Significance ◽  
Functional Studies ◽  
Variants Of Unknown Significance ◽  
Manual Curation ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Whole Exome Sequencing Data

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 ACMG guidelines for variant interpretation, we curated 1,547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 AML patients (13.6%) in 34 genes. 41% of variants were in DNA damage response genes, and the most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). 44% of the pathogenic germline variants were in genes considered clinically actionable (tier 1). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, six patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in-silico approach that applies ACMG/AMP curation in an automated manner using the tool for assessment and prioritization in exome studies (TAPES), which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

scholarly journals Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing

2018 ◽  
Vol 28 (1) ◽  
pp. 123-126 ◽  
Author(s):  
Nutsuchar Wangtiraumnuay ◽  
Jenina Capasso ◽  
Mai Tsukikawa ◽  
Alex Levin ◽  
Esther Biswas-Fiss
Keyword(s):  
Amino Acids ◽  
Genetic Testing ◽  
Protein Structure ◽  
Protein Function ◽  
Macular Dystrophy ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Variants Of Unknown Significance ◽  
Novel Variants ◽  
Unknown Significance

Purpose: Mutations in the ABCA4 gene result in a broad spectrum of severe retinal degeneration, including Stargardt macular dystrophy, fundus flavimaculatus, autosomal recessive retinitis pigmentosa, and cone-rod dystrophy. In addition to the detection of well-characterized mutations, genetic testing frequently yields novel variants of unknown significance. The purpose of this report is to describe an approach to aid in the assessment of genetic variants of unknown significance. Case report: We report an 11-year-old girl with Stargardt disease harboring novel compound heterozygous deletions of ABCA4 (c.850_857delATTCAAGA and c.6184_6187delGTCT). The pathogenicity of these variants was otherwise unknown. Both deletions introduce premature stop codons and are localized within the open reading frame of ABCA4. The c.850_857delATTCAAGA occurs early in the gene and leads to a significantly truncated protein of only 317 amino acids. The c.6184_6187delGTCT, is localized to the 3’ terminus of the ORF and results in removal of the last 161 out of 2,273 amino acids of ABCA4, including the VFVNFA motif, which has been shown to be critical in ABCA4 protein function. Homology-based protein modeling of ABCA4 harboring this deletion suggests significant alterations in the protein structure and function. Conclusions: Our analyses allowed us to classify novel variants in ABCA4 as being clearly loss-of-function mutations, and thus pathogenic variants. In cases of variants of unknown significance, appraising the protein structure-function consequences of genetic mutations using in silico tools may help to predict the clinical importance of variants of uncertain pathogenicity.

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