scholarly journals The First Korean Case of SLC12A3 Aberrant Skipping of Two Exons Detected by RNA Splicing Analysis

2021 ◽  
Vol 11 (2) ◽  
pp. 210-213
Author(s):  
Kiwoong Ko ◽  
Jong-Won Kim
Keyword(s):  
Rna Splicing ◽  
Autosomal Recessive ◽  
Gitelman Syndrome ◽  
Recessive Trait ◽  
Aberrant Splicing ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Exonic Variant ◽  
Uncertain Significance ◽  
Potential Pathogenicity

Gitelman syndrome is a salt-losing tubular disorder that is transmitted as an autosomal recessive trait. Variants in the <i>SLC12A3</i> gene are found in the majority of Gitelman syndrome patients. A 26-year-old woman visited the genetic counseling clinic. Her fiancé was a known Gitelman syndrome patient who was previously diagnosed with 2 pathogenic variants in <i>SLC12A3</i>. In advance of marriage and future family planning, she wanted to perform genetic testing of <i>SLC12A3</i>. A silent exonic variant c.1050G&#x3e;A was found, and multiple splice site in silico algorithms predicted this variant to have potential alteration of splicing. This variant was classified as “variant of uncertain significance,” and RNA splicing analysis was additionally performed. RNA splicing analysis showed aberrant splicing of exon 7–8 skipping. The result points out the potential pathogenicity of this variant, which should be considered a candidate of variant reclassification in the future. We highly recommend the performance of additional RNA splicing analysis, especially for silent variants predicted to have potential alteration of splicing.

scholarly journals Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi-Heng Zeng ◽  
Bi-Wei Lin ◽  
Hui-Zhen Su ◽  
Xin-Xin Guo ◽  
Yun-Lu Li ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Psychiatric Symptoms ◽  
Clinical Spectrum ◽  
Recessive Trait ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Primary Familial Brain Calcification ◽  
Brain Calcification ◽  
Uncertain Significance ◽  
Chinese Cohort

Primary familial brain calcification (PFBC) is a progressive neurological disorder manifesting as bilateral brain calcifications in CT scan with symptoms as parkinsonism, dystonia, ataxia, psychiatric symptoms, etc. Recently, pathogenic variants in MYORG have been linked to autosomal recessive PFBC. This study aims to elucidate the mutational and clinical spectrum of MYORG mutations in a large cohort of Chinese PFBC patients with possible autosomal recessive or absent family history. Mutational analyses of MYORG were performed by Sanger sequencing in a cohort of 245 PFBC patients including 21 subjects from 10 families compatible with a possibly autosomal-recessive trait and 224 apparently sporadic cases. In-depth phenotyping and neuroimaging features were investigated in all patients with novel MYORG variants. Two nonsense variants (c.442C &gt; T, p. Q148*; c.972C &gt; A, p. Y324*) and two missense variants (c.1969G&gt;C, p. G657R; c.2033C &gt; G, p. P678R) of MYORG were identified in four sporadic PFBC patients, respectively. These four novel variants were absent in gnomAD, and their amino acid were highly conserved, suggesting these variants have a pathogenic impact. Patients with MYORG variants tend to display a homogeneous clinical spectrum, showing extensive brain calcification and parkinsonism, dysarthria, ataxia, or vertigo. Our findings supported the pathogenic role of MYORG variants in PFBC and identified two pathogenic variants (c.442C &gt; T, c.972C &gt; A), one likely pathogenic variant (c.2033C &gt; G), and one variant of uncertain significance (c.1969G&gt;C), further expanding the genetic and phenotypic spectrum of PFBC-MYORG.

scholarly journals Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis

2022 ◽  
Vol 8 (1) ◽  
pp. e654
Author(s):  
Melissa Nel ◽  
Amokelani C. Mahungu ◽  
Nomakhosazana Monnakgotla ◽  
Gerrit R. Botha ◽  
Nicola J. Mulder ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Population Group ◽  
Genetic Ancestry ◽  
Familial Case ◽  
Data Sets ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Sporadic Als ◽  
Uncertain Significance ◽  
Lateral Sclerosis

Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.

scholarly journals A scalable EHR-based approach for phenotype discovery and variant interpretation for hereditary cancer genes

2021 ◽  
Author(s):  
Chenjie Zeng ◽  
Lisa A Bastarache ◽  
Ran Tao ◽  
Eric Venner ◽  
Scott Hebbring ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Meta Analysis ◽  
Genetic Disorders ◽  
Genomic Medicine ◽  
Risk Scores ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Emerge Network ◽  
Uncertain Significance ◽  
Potential Pathogenicity

Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1 ×10-125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.

Germline pathologic mutations and cancer family history in prostate cancer patients.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 378-378
Author(s):  
Marcus Marie Moses ◽  
Elisa Ledet ◽  
Emma M. Ernst ◽  
Patrick Cotogno ◽  
Joshua Schiff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Family History ◽  
San Francisco ◽  
Treatment Options ◽  
Distant Metastases ◽  
Cancer Center ◽  
Chi Square ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance

378 Background: Prostate cancer (PCa) patients (pts) with metastases and/or strong family history (FH) of cancer (Ca) are at higher risk of a germline mutation. The identification of alterations in PCa pts may be important for risk stratification as well as personalizing treatment options. The goal of this study was characterization of FH and pathogenic variants (PV) detected in PCa pts, with both localized and metastatic disease. Methods: 300 PCa pts from Tulane Cancer Center underwent germline testing. 265 Caucasian (C) and 35 African-Americans (AA) were tested and met the NCCN criteria for testing and/or had distant metastases (mets). Germline genetic testing was done via commercial panels (30-80 genes) (Invitae. San Francisco, Ca). PCa pts had extensive FH screening. Clinical annotation included age at diagnosis (dx), race, and presence of mets at any time. Chi square tests were used to compare clinical correlates and PVs. Results: Of the 300 pts tested, 182 pts (60.6%) had mets and 118 (39.4%) did not. 41 pts (13.6%) had ≥ 1 germline pathogenic variant (PV) and 161 pts (53.6%) had ≥ 1 germline variant of uncertain significance (VUS). PVs were detected in BRCA2 (n = 10), MUTYH (n = 8), CHEK2 (n = 6), BRCA1 (n = 4), ATM (n = 4), TP53 (n = 3), PMS2 (n = 2), BLM (n = 2), MITF (n = 2), NBN (n = 1), and RAD51D (n = 1). MUTYH and MITF are not known to be linked to prostate cancer. There was no significant relationships in FH PCa and FH non-PCa in regard to likelihood of a PV (p = .86 and p = .18). Of the 300 pts tested, 136 pts (45.3%) had PCa FH, 131 pts (43.6%) had breast Ca FH, 61 pts (20.3%) had lung Ca FH, 61 pts (20.3%) had colon Ca FH, 37 pts (12.3%) had pancreatic Ca FH, and 32 pts (10.6%) had ovarian Ca FH. 45.6% of C men (n = 121) and 42.8% of AA men (n = 15) had PCa FH. Pts with a non-PCa FH (n = 255) were 1.37 times more likely to develop mets (p = .01168). The median age of dx were 61 for PV pts, 62 for VUS pts, and 61 for negative pts (non-significant). 21/182 pts with mets (11.5%) had a PV; 8/182 (4.4%) pts with mets had a BRCA2 PV. Conclusions: In metastatic patients, FH of prostate cancer alone cannot predict those with PV. The most common Cas observed in these pts were breast, lung, colon and pancreatic. A larger cohort is needed to fully characterize and understand the co-segregation of PCa with other Cas.

scholarly journals Novel Loss-of-Function Mutations in COCH Cause Autosomal Recessive Nonsyndromic Deafness

2020 ◽  
Author(s):  
Kevin T Booth ◽  
Amama Ghaffar ◽  
Muhammad Rashid ◽  
Luke T Hovey ◽  
Mureed Hussain ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Rna Splicing ◽  
Autosomal Recessive ◽  
Dominant Negative ◽  
Nonsyndromic Hearing Loss ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Exon Splicing ◽  
Coding Variants

AbstractCOCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly deafness in mice and humans. Two forms of deafness are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used mini-gene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA-splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA-splicing, and highlights the need to investigate the effect of coding variants on RNA-splicing.

scholarly journals Predicting RNA splicing from DNA sequence using Pangolin

2021 ◽  
Author(s):  
Tony Zeng ◽  
Yang I Li
Keyword(s):  
Deep Learning ◽  
Dna Sequence ◽  
Rna Splicing ◽  
Rare Variants ◽  
Sequence Data ◽  
Learning Approaches ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
The Impact

Recent progress in deep learning approaches have greatly improved the prediction of RNA splicing from DNA sequence. Here, we present Pangolin, a deep learning model to predict splice site strength in multiple tissues that has been trained on RNA splicing and sequence data from four species. Pangolin outperforms state of the art methods for predicting RNA splicing on a variety of prediction tasks. We use Pangolin to study the impact of genetic variants on RNA splicing, including lineage-specific variants and rare variants of uncertain significance. Pangolin predicts loss-of-function mutations with high accuracy and recall, particularly for mutations that are not missense or nonsense (AUPRC = 0.93), demonstrating remarkable potential for identifying pathogenic variants.

Exome Sequencing Highlights a Potential Role for Concealed Cardiomyopathies in Youthful Sudden Cardiac Death

2021 ◽  
Author(s):  
Raquel Neves ◽  
David J. Tester ◽  
Michael A. Simpson ◽  
Elijah R. Behr ◽  
Michael J. Ackerman ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Strong Evidence ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Medical Genetics ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Genetic Test Results ◽  
Uncertain Significance ◽  
Genetics And Genomics

Background: Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident. Methods: Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (49 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, n=141 456 individuals]) nonsynonymous variants identified in 24 ClinGen adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines. Results: Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; P =0.05) SCA survivors and 8 out of 68 (11.8%; P =0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, P <0.02) SUD cases without ventricular fibrosis. Conclusion: Our data further supports the inclusion of strongevidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.

scholarly journals Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis

2021 ◽  
Author(s):  
Paola Nix ◽  
Erin Mundt ◽  
Bradford Coffee ◽  
Elizabeth Goossen ◽  
Bryan M. Warf ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Case Series ◽  
Cancer History ◽  
Rna Analysis ◽  
Pathogenic Variants ◽  
Conflicting Evidence ◽  
Increased Risk ◽  
Splicing Variants ◽  
Uncertain Significance ◽  
In Silico Models

AbstractA substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations (BRCA2 c.68-3T>G, c.68-2A>G, c.425G>T, c.8331+2T>C). Evidence supporting a pathogenic classification is available for each variant, including in silico models, absence in population databases, and published functional data. However, comprehensive RNA analysis showed that some functional transcript may be produced by each variant. BRCA2 c.68-3T>G results in a partial splice defect. For BRCA2 c.68-2A>G and c.425G>T, aberrant splicing was shown to produce a potentially functional, in-frame transcript. BRCA2 c.8331+2T>C may utilize a functional GC donor in place of the wild-type GT donor. The severity of cancer history for carriers of these variants was also assessed using a history weighting algorithm and was not consistent with pathogenic controls (carriers of known pathogenic variants in BRCA2). Due to the conflicting evidence, our laboratory classifies these BRCA2 variants as variants of uncertain significance. This highlights the importance of evaluating new and existing evidence to ensure accurate variant classification and appropriate patient care.

scholarly journals Classification of the canonical splice alteration MUTYH c.934-2A>G is likely benign based on RNA and clinical data

2021 ◽  
pp. mcs.a006152
Author(s):  
Felicia Hernandez ◽  
Blair Rene Conner ◽  
Marcy E. Richardson ◽  
Holly LaDuca ◽  
Elizabeth Chao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Colonic Polyps ◽  
Autosomal Recessive Disorder ◽  
Splice Defect ◽  
Critical Domain ◽  
Variant Of Uncertain Significance ◽  
Aberrant Transcript ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Exon 11

MUTYH-associated polyposis (MAP) is an autosomal recessive disorder characterized by the development of multiple adenomatous colonic polyps and an increased lifetime risk of colorectal cancer. Germline biallelic pathogenic variants in MUTYH are responsible for MAP. The MUTYH c.934-2A>G (NM_001128425.1) variant, which is also known as c.850-2A>G for NM_001048174.2, has been identified in our laboratory in more than 800 patients, including homozygous and compound heterozygote carriers. The variant was initially classified as a variant of uncertain significance (VUS) due to lack of a MAP phenotype in biallelic carriers. In two unrelated female patients who were heterozygous carriers of this variant, further testing by RNA sequencing identified an aberrant transcript with a deletion of 9 nucleotides at the start of exon 11 (MUTYH r.934_942del9). This event is predicted to lead to an in-frame loss of 3 amino acids in a non-critical domain of the protein. This was the only splice defect identified in these patients which was not present in the controls and the aberrant transcript is derived exclusively from the variant allele, strongly supporting the cause of this splice defect as being the intronic variant, MUTYH c.934-2A>G. The splicing analysis demonstrating a small in-frame skipping of 3 amino acids in a non-critical domain along with the absence of a MAP phenotype in our internal cohort of biallelic carriers provides evidence that the variant is likely benign and not of clinical significance.

scholarly journals Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zuzana Pavlenkova ◽  
Lukas Varga ◽  
Silvia Borecka ◽  
Miloslav Karhanek ◽  
Miloslava Huckova ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Sensorineural Hearing ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Causal Genes ◽  
Uncertain Significance

AbstractThe genetic heterogeneity of sensorineural hearing loss (SNHL) is a major hurdle to the detection of disease-causing variants. We aimed to identify underlying causal genes associated with mid-frequency hearing loss (HL), which contributes to less than about 1% of SNHL cases, by whole exome sequencing (WES). Thirty families segregating mid-frequency SNHL, in whom biallelic GJB2 mutations had been previously excluded, were selected from among 851 families in our DNA repository of SNHL. DNA samples from the probands were subjected to WES analysis and searched for candidate variants associated with SNHL. We were able to identify the genetic aetiology in six probands (20%). In total, we found three pathogenic and three likely pathogenic variants in four genes (COL4A5, OTOGL, TECTA, TMPRSS3). One more proband was a compound heterozygote for a pathogenic variant and a variant of uncertain significance (VUS) in MYO15A gene. To date, MYO15A and TMPRSS3 have not yet been described in association with mid-frequency SNHL. In eight additional probands, eight candidate VUS variants were detected in five genes (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR). Seven of these 16 variants have not yet been published or mentioned in the available databases. The most prevalent gene was TECTA, identified in 23% of all tested families. Furthermore, we confirmed the hypothesis that a substantive portion of cases with this conspicuous audiogram shape is a consequence of a genetic disorder.

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