Faculty Opinions recommendation of Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes.

2019 ◽  
Author(s):  
Buz Jinnah
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Diagnosis ◽  
Whole Genome

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.

scholarly journals The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants

2017 ◽  
Author(s):  
Josh E. Petrikin ◽  
Julie A. Cakici ◽  
Michelle M. Clark ◽  
Laurel K. Willig ◽  
Nathaly M. Sweeney ◽  
...  
Keyword(s):  
Intensive Care ◽  
Whole Genome Sequencing ◽  
Intensive Care Units ◽  
Genome Sequencing ◽  
Genetic Diagnosis ◽  
Pediatric Intensive Care ◽  
Genomic Sequencing ◽  
Whole Genome ◽  
Randomized Controlled ◽  
Standard Tests

AbstractImportanceGenetic disorders, including congenital anomalies, are a leading cause of morbidity and mortality in infants, especially in neonatal and pediatric intensive care units (NICU and PICU). While genomic sequencing is useful for diagnosis of genetic diseases, results are usually reported too late to guide inpatient management.ObjectiveTo test the hypothesis that rapid whole genome sequencing (rWGS) increases the proportion of infants in NICUs and PICUs receiving a genetic diagnosis within 28 days.DesignAn investigator-initiated, partially blinded, pragmatic, randomized controlled study with enrollment from October 2014 - June 2016, and follow up until December 2016.SettingA regional neonatal and pediatric intensive care unit in a tertiary referral childrens hospital.ParticipantsSixty five of 129 screened families with infants aged less than four months, in neonatal and pediatric intensive care units, and with illnesses of unknown etiology, completed the study.InterventionParent and infant trio rWGS.Main Outcome and MeasureThe hypothesis and end-points were formulated a priori. The primary end-point was rate of genetic diagnosis within 28 days of enrollment or first standard test order.ResultsTwenty six female proband infants, 37 male infants, and two infants of undetermined sex were randomized to receive rWGS plus standard tests (n=32, cases) or standard tests alone (n=33, controls). The study was terminated early due to loss of equipoise: 63% (21) controls received genomic sequencing as standard tests. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days to be higher in cases (31%, ten of 32) than controls (3%, one of 33; difference, 28% [95% CI, 10% to 46%]; p=0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, seven of 22) than controls (0%, zero of 23; difference, 32% [95% CI, 11% to 53%]; p=0.004). Age at diagnosis (median in cases 25 days, range 14-90 days vs median in controls 130 days, range 37-451) and time to diagnosis (median in cases thirteen days, range 1-84 days vs median in controls 107 days, range 21-429 days) were significantly less in cases than controls (p=0.04).CONCLUSIONSrWGS increased the proportion of infants in a regional NICU and PICU who received a timely diagnosis of a genetic disease. Additional, adequately powered studies are needed to determine whether accelerated diagnosis is associated with improved outcomes in this setting. ClinicalTrials.gov Identifier: NCT02225522.

scholarly journals Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zeinab Fadaie ◽  
Laura Whelan ◽  
Tamar Ben-Yosef ◽  
Adrian Dockery ◽  
Zelia Corradi ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Variants ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Retinal Diseases ◽  
Structural Variants ◽  
Pathogenic Variants ◽  
Coding Variants

AbstractInherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.

scholarly journals Whole genome sequencing of a sporadic primary immunodeficiency cohort

2018 ◽  
Author(s):  
James E. D. Thaventhiran ◽  
Hana Lango Allen ◽  
Oliver S. Burren ◽  
William Rae ◽  
Daniel Greene ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Primary Immunodeficiency ◽  
Genome Wide Association Study ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Common Variants ◽  
Phenotypic Complexity ◽  
A Genome

AbstractPrimary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.

scholarly journals Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

2019 ◽  
Vol 69 ◽  
pp. 111-118 ◽  
Author(s):  
Kishore R. Kumar ◽  
Ryan L. Davis ◽  
Michel C. Tchan ◽  
G.M. Wali ◽  
Neil Mahant ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Diagnosis ◽  
Whole Genome

scholarly journals Long‐read whole‐genome sequencing for the genetic diagnosis of dystrophinopathies

2020 ◽  
Vol 7 (10) ◽  
pp. 2041-2046
Author(s):  
Zhiying Xie ◽  
Chengyue Sun ◽  
Siwen Zhang ◽  
Yilin Liu ◽  
Meng Yu ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Long Read

scholarly journals Whole-genome sequencing of rare disease patients in a national healthcare system

2019 ◽  
Author(s):  
Willem H Ouwehand ◽  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Healthcare System ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Phenotypic Data ◽  
National Healthcare ◽  
National Healthcare System

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

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