scholarly journals Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing

2020 ◽  
Vol 6 (3) ◽  
pp. a003970
Author(s):  
Isabelle Thiffault ◽  
Andrea Atherton ◽  
Bryce A. Heese ◽  
Ahmed T. Abdelmoity ◽  
Kailash Pawar ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Pathogenic Variants

scholarly journals A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

2020 ◽  
Vol 29 (6) ◽  
pp. 967-979 ◽  
Author(s):  
Revital Bronstein ◽  
Elizabeth E Capowski ◽  
Sudeep Mehrotra ◽  
Alex D Jansen ◽  
Daniel Navarro-Gomez ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Diagnosis ◽  
Genetic Diagnostics ◽  
Whole Genome ◽  
Unique Challenge ◽  
Coding Regions ◽  
Pathogenic Variants ◽  
Number Of Patients ◽  
Coding Variants

Abstract Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful, an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient-induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) transcriptome analysis. With this approach, we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.

Author response for "Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability"

2018 ◽  
Author(s):  
Ann-Charlotte Thuresson ◽  
Cecilia Soussi Zander ◽  
Jin J. Zhao ◽  
Jonatan Halvardson ◽  
Khurram Maqbool ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Author Response ◽  
Whole Genome ◽  
Pathogenic Variants

Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13113-e13113
Author(s):  
Howard John Lim ◽  
Kasmintan A Schrader ◽  
Sean Young ◽  
Jessica Nelson ◽  
Alexandra Fok ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genomic Research ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.

scholarly journals Exploring the Missing Heritability in Subjects With Hearing Loss, Enlarged Vestibular Aqueducts, and A Single or No Pathogenic SLC26A4 Variant

2021 ◽  
Author(s):  
Jeroen Smits ◽  
Suzanne E. de Bruijn ◽  
Cornelis P. Lanting ◽  
Jaap Oostrik ◽  
Luke O’Gorman ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genome Mapping ◽  
Copy Number Variants ◽  
Whole Genome ◽  
Missing Heritability ◽  
Vestibular Aqueduct ◽  
Pathogenic Variants ◽  
Long Read

Abstract Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype-phenotype correlation, a significant part of SLC26A4 cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, short- and long-read whole genome sequencing and optical genome mapping were performed. We found a previously described EVA-associated haplotype (Caucasian EVA (CEVA)) to be significantly enriched in our M1 patient cohort. The haplotype was also present in two M0 cases. Despite extensive genetic analyses, we were not able to prioritize any of the variants present within the haplotype as the likely pathogenic defect, and therefore additional analyses addressing the defect(s) at the RNA, protein, or epigenetic level are required. Whole genome sequencing also revealed splice-altering SLC26A4 variants in two M1 cases, which are now genetically explained, but no deep-intronic or copy number variants. With these findings, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases.

scholarly journals Germline and Tumor Whole Genome Sequencing as a Diagnostic Tool to Resolve Suspected Lynch Syndrome

2020 ◽  
Author(s):  
Bernard J. Pope ◽  
Mark Clendenning ◽  
Christophe Rosty ◽  
Khalid Mahmood ◽  
Peter Georgeson ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Gene Mutations ◽  
Gene Promoter ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Tumor Sequencing ◽  
Mmr Deficiency ◽  
Complex Structural

AbstractBackgroundPeople who develop mismatch repair (MMR) deficient cancer in the absence of a germline MMR gene pathogenic variant or hypermethylation of the MLH1 gene promoter in their tumor are classified as having suspected Lynch syndrome (SLS). We applied germline whole genome sequencing (WGS) and targeted and genome-wide tumor sequencing approaches to identify the underlying cause of tumor MMR-deficiency in SLS.MethodsGermline WGS was performed on 14 cancer-affected people with SLS, including two sets of first-degree relatives. Tumor tissue was sequenced for somatic MMR gene mutations by targeted, whole exome sequencing or WGS. Germline pathogenic variants, including complex structural rearrangements and non-coding variants, were assessed for the MMR genes. Tumor mutation burden and mutational signatures.ResultsGermline WGS identified pathogenic MMR variants in 3 of the 14 (21.4%) SLS cases including a 9.5Mb inversion disrupting exons 1-7 of MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8/11 (72.7%) tumors tested, supporting a non-inherited cause of tumor MMR-deficiency. In the second mother-daughter pair, the combined analysis of germline and tumor by WGS supported a somatic rather than inherited cause of their tumor MMR-deficiency, through presence of double somatic MSH2 mutations in their respective tumors.ConclusionGermline WGS of people with SLS improved the identification of Lynch syndrome. When coupled with tumor sequencing, >70% of the people with SLS were resolved as having double somatic MMR mutations and a non-inherited cause for their tumor MMR-deficiency.

scholarly journals An oligogenic risk model for Gilles de la Tourette syndrome based on whole-genome sequencing data

2021 ◽  
Author(s):  
Malgorzata Borczyk ◽  
Jakup P Fichna ◽  
Marcin Piechota ◽  
Sławomir Gołda ◽  
Michał Korostyński ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Candidate Genes ◽  
Tourette Syndrome ◽  
Genome Sequencing ◽  
Risk Model ◽  
Neurodevelopmental Disorder ◽  
Tic Disorders ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Pathogenic Variants

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder from the spectrum of tic disorders (TDs). GTS and other TDs have a substantial genetic component with the heritability estimated at between 60 and 80%. Here we propose an oligogenic risk model of GTS and other TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients and their families (n=185). The model is based on the overrepresentation of putatively pathogenic coding and non-coding genetic variants in genes selected from a set of 86 genes previously suggested to be associated with GTS. Based on the variant overrepresentation (SKAT test results) between unrelated GTS patients and controls based on gnomAD database allele frequencies five genes (HDC, CHADL, MAOA, NAA11, and PCDH10) were selected for the risk model. Putatively pathogenic variants (n = 98) with the median allele frequency of ~0.04 in and near these genes were used to build an additive classifier which was then validated on the GTS patients and their families. This risk model successfully assigned individuals from 22 families to either healthy or GTS groups (AUC-ROC = 0.6, p < 0.00001). These results were additionally validated using the GTS GWAS data from the Psychiatric Genomic Consortium. To investigate the GTS genetics further we identified 32 genes from the list of 86 genes as candidate genes in 14 multiplex families, including NEGR1 and NRXN with variants overrepresented in multiple families. WGS data allowed the construction of an oligogenic risk model of GTS based on possibly pathogenic variants likely contributing to the risk of GTS and TDs. The model includes putatively deleterious rare and non-coding variants in and near GTS candidate genes that may cooperatively contribute to GTS etiology and provides a novel approach to the analysis of clinical WGS data.

scholarly journals Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant

2021 ◽  
Author(s):  
Jeroen J. Smits ◽  
Suzanne E. de Bruijn ◽  
Cornelis P. Lanting ◽  
Jaap Oostrik ◽  
Luke O’Gorman ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genome Mapping ◽  
Whole Genome ◽  
Missing Heritability ◽  
Single Nucleotide Variants ◽  
Vestibular Aqueduct ◽  
Pathogenic Variants ◽  
Long Read

AbstractPathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype–phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4. We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.

scholarly journals Evaluation of the Molecular Pathogenesis of Adrenocortical Tumors by Whole-Genome Sequencing

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A68-A68
Author(s):  
Kerstin Neininger ◽  
Patrick May ◽  
Barbara Altieri ◽  
Juliane L Lippert ◽  
Kirsten Roomp ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Whole Genome ◽  
Cortisol Secretion ◽  
Structural Variations ◽  
Driver Genes ◽  
Pathogenic Variants ◽  
Autonomous Cortisol Secretion

Abstract Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Our aim was to identify novel genetic alterations in adrenocortical adenomas (ACA) without somatic mutations in known driver genes. Whole-genome sequencing was performed on 26 ACA/blood-derived DNA pairs without driver mutations in PRKACA, GNAS and CTNNB1 genes at previous WES (ENSAT study JCEM 2016). These included 12 cortisol-producing adenomas with Cushing syndrome (CS-CPAs), 7 with mild autonomous cortisol secretion (MACS-CPAs), and 7 endocrine-inactive ACAs (EIAs). Seven adrenocortical carcinomas (ACC) were added to the cohort. We developed a bioinformatics pipeline for a comprehensive genome analysis and to reveal differences in variant distribution. Strelka, VarScan2 and ANNOVAR software and an in-house confidence score were used for variant calling and functional annotation. Combined Annotation-Dependent-Depletion (CADD) values were used to prioritize pathogenic variants. Additional focus relied on variants in pathogenically known pathways (Wnt/β-catenin, cAMP/PKA pathway). NovoBreak algorithm was applied to discover structural variations. Two hypermutated CS-CPA samples were excluded from further analysis. Using different filters, we detected variants in driver genes not observed at WES (one p.S45P in CTNNB1 and one p.R206L in PRKACA in two different CS-CPAs). In total, we report 179,830 variations (179,598 SNVs; 232 indels) throughout all samples, being more abundant in ACC (88,954) compared to ACA (CS-CPAs: 31,821; MACS-CPAs: 35,008; EIAs: 29,963). Most alterations were in intergenic (&gt;50%), followed by intronic and ncRNA intronic regions. A total of 32 predicted pathogenic variants were found in both coding (CADD values ≥ 15) and non-coding (CADD values ≥ 5) regions. We found 3,301 possibly damaging and recurrent variants (intergenic mutations removed) (CS-CPAs: 1,463; MACS-CPAs: 1,549; EIAs: 1,268; ACC: 1,660), mostly accumulated in intronic regions. Some of these were detected in members of the Wnt/β-catenin (CS-CPAs: 6; MACS-CPAs: 2; EIA: 1) and cAMP/PKA (CS-CPAs: 6; MACS-CPAs: 7; EIA: 4) pathways (e.g. ADCY1, ADCY2, GNA13, PDE11A). We also found a slightly higher number of structural variations in EIA (3,620) and ACC (3,486) compared to CS-CPAs (977) and MACS-CPAs (2,119). In conclusion, still unrevealed genetic alterations, especially in intronic regions, may accompany early adrenal tumorigenesis and/or autonomous cortisol secretion.

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