Variants were identified with the use of Atlas-SNP and Atlas-Indel.16 ESP denotes ESP5400 data from the National Heart, Lung, and Blood Institute GO Exome Sequencing Project, HGMD Human Gene Mutation Database, MAF minor allele frequency, TG the 1000 Genomes Project, and VUS variants of unknown clinical significance. Genetic sequencing is expected to greatly improve the rate of diagnoses for rare conditions in the future. Bainbridge MN, Hu H, Muzny DM, et al. Osteocraniostenosis (OCS) was first described in 1994 and was noted to be a perinatally lethal condition with premature closure of cranial sutures and gracile bones . This patient carried a mutation in SYNGAP1, 31 which is associated with a newly recognized nonsyndromic mental retardation that may not have been identified by conventional genetic testing. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. By using this website, you agree to our The cases are from a consecutive set of clinical cases referred for exome sequencing from clinics at a single university health system as well as from outside referring … https://doi.org/10.1186/s12881-019-0939-z, DOI: https://doi.org/10.1186/s12881-019-0939-z. Questions about cost-effectiveness, accuracy, yield, and effective integration of genome-based diagnosis in medical care must be addressed in future studies and will require prospective study designs. Abstract Whole-exome sequencing is increasingly used for diagnosis and identification of appropriate therapies in patients. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. Moreover, interrogation of the exome may uncover secondary findings, complicating reporting.13 We analyzed 250 unselected, consecutive cases with the use of clinical whole-exome sequencing in a laboratory certified by the College of American Pathologists (CAP) and the Clinical Laboratory Improvement Amendments (CLIA) program. Terms and Conditions, Shevell M, Ashwal S, Donley D, et al. 2). Global report on birth defects: the hidden toll of dying and disabled children. All putative causative alleles were subjected to extensive literature and database searches, and the results were discussed in roundtable sessions by laboratory directors and physicians with appropriate clinical expertise. Remaining variants were compared computationally with the list of reported mutations from the Human Gene Mutation Database.17 Variants in this database with a minor allele frequency of less than 5% according to either the 1000 Genomes Project18 or the ESP5400 data of the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (http://evs.gs.washington.edu/EVS) were retained. The datasets analysed during the current study are available in the Decipher repository. Genet Med 2012;14:399-404, 14. The authorized source of trusted medical research and education for the Chinese-language medical community. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. The results of whole-exome sequencing were sent in a two-tiered report to the referring physician within approximately 15 weeks after the test was requested (Table 2). We initiated clinical testing with whole-exome sequencing in October 2011. Supported in part by grants from the National Human Genome Research Institute (U54-HG003273, to Dr. Gibbs; and U01 HG006485-01, to Dr. Plon). Rauch A, Wieczorek D, Graf E, et al. Approximately 200,000 to 400,000 single-nucleotide variants and small insertion and deletion changes were identified in each patient's personal genome by comparison with the current reference haploid human genome sequence (human genome 19). Exome sequencing of the UK Biobank cohort. Beyond the technical challenges of the genomic assay and bioinformatic analyses of massive amounts of data, the diagnostic yield in a clinical laboratory setting for unselected patients with a broad range of phenotypes is unknown. 2018;137(2):175–81. In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Kohane IS, Hsing M, Kong SW. Taxonomizing, sizing, and overcoming the incidentalome. We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. This article was published on October 2, 2013, at NEJM.org. Prenatal WES relies on this sonographic evidence to help select the most appropriate Human Phenotypic Ontology (HPO) terms in order to target the analysis appropriately. Lancet. The first trimester scan was normal and combined screening showed low risk for a major chromosomal abnormality. Laboratory coordinators monitored the submission of these forms and ensured receipt before interpretation of the data from whole-exome sequencing. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. Targeted WES accurately diagnosed a lethal skeletal dysplasia that had not been suspected from the ultrasound features. title = "Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience", abstract = "Objective To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic … Patterns of familial segregation were tested to identify expected modes of inheritance, and the similarity of identified phenotypes with those described in previous reports was considered (Figure 1). In conclusion, this study shows that clinical exome sequencing is a non-invasive, highly effective tool for genetic diagnosis if the program is supported by careful candidate selection. De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Following the lethal skeletal dysplasia diagnosis, the couple made the difficult decision to end the pregnancy. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. volume 21, Article number: 7 (2020) Cheung SW, Shaw CA, Yu W, et al. Nat Genet 2010;42:1109-1112, 9. Whole-exome sequencing and analysis protocols developed by the Human Genome Sequencing Center at the Baylor College of Medicine were adapted for the clinical test of whole-exome sequencing. Stankiewicz P, Lupski JR. N Engl J Med 2012;367:1921-1929, 12. For changes that are not in the Human Gene Mutation Database, synonymous variants, intronic variants that were more than 5 bp from exon boundaries (which are unlikely to affect messenger RNA splicing), and common variants (minor allele frequency, >1%) were also discarded (Figure 1). Objective To determine the molecular diagnostic yield of exome sequencing … The interpretation of clinical whole-exome sequencing data at our center was performed by a team of persons representing several areas of expertise. In contrast to whole-genome sequencing, which analyzes the 3 billion base pairs in the human genome, whole-exome sequencing … For WES to be used successfully, good phenotyping is essential. The couple were counselled about the uncertainty of the child’s prognosis and offered targeted whole exome sequencing (WES). Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. Am J Hum Genet 1988;42:677-693, 3. TH, a clinical geneticist analysed the data and confirmed phenotype genotype correlation. Cookies policy. Objective To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Unger S, Gorna M, Le Bechec A, Vale-Pereira S, Bedeschi M, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafé L, Superti-Furga A. FAM111A mutations result in Hypoparathyroidism and impaired skeletal development. Deardorff MA, Bando M, Nakato R, et al. and the Human Genome Sequencing Center (D.M.M., J.G.R., M.N.B., P.P., M.W., Y.D., J.R.L., R.A.G. Although most patients who receive a diagnosis on the basis of whole-exome sequencing are likely to have rare genetic diseases, it was expected that some of the diagnoses would be relatively common syndromes. Phenocopies are cases for which exome sequencing–derived genetic diagnosis differs from the presumed clinical diagnosis. Objective To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Reassessment of these cases in an “exome clinic” that involved comprehensive specialist review of all available clinical information as well as the exome sequencing data on each patient led to the recognition of false-positive diagnoses in 5 patients and additional genetic diagnoses in 16, raising the rate of definitive diagnosis to 43%. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. The remaining patient, for whom parental samples were not available, carried an apparently homozygous, common, disease-causing mutation. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. The Purdue Pharma Opioid Settlement — Accountability, or Just the Cost of Doing Business? Mutation Type No. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Here, we describe the first prenatal diagnosis of OCS. Petrovski S, Aggarwal V, Wou K, Bier L. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Other technical limitations may result from the presence of multiple pseudogenes or repetitive regions that obscure the specific copy to which the variant maps.35. In this study, we … Hamdan FF, Gauthier J, Spiegelman D, et al. All authors read and approved the final manuscript. Exome sequencing identifies PEX6 mutations in three cases diagnosed with Retinitis Pigmentosa and hearing impairment Whole-genome sequencing for optimized patient management. The expanded set of variants in tier two were provided if they were requested by the physician and if additional consent for tier-two reporting of results had been obtained from the patient. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. Parental samples, if available, were also analyzed by means of Sanger sequencing to determine whether the mutated allele had been transmitted and, if so, by whom. Stenson PD, Mort M, Ball EV, et al. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A cloverleaf skull is often associated with OCS. 2018;38(1):20–5. 2013;86(4):394–5. Genome Med 2013;5:57-57. Exome sequencing allows sequencing of portions of the genome over at least 20 times as many samples compared to whole genome sequencing, at the same cost. Variants that were deemed clinically significant were confirmed by means of Sanger sequencing. In individuals with CDH+, the … Whole exome sequencing … 1994;31(10):772–778. Am J Hum Genet 2012;90:565-572, 24. Part of All patients had undergone prior genetic testing, which consisted of chromosomal microarray analysis,3,4 metabolic screening, DNA sequencing studies, or a combination of these tests. Clinical confirmation is often the only means of establishing the veracity of the diagnosis. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). It was explicit in the consent that we would not find or report incidental findings. Springer Nature. Whole-exome sequencing has also proved useful in the characterization of patients with multiple diagnoses. https://decipher.sanger.ac.uk/browser#q/FAM111A/location/11:58791366-59041366, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, https://doi.org/10.1186/s12881-019-0939-z, Clinical-Molecular Genetics and Cytogenetics. In our laboratory, the positive rate for single-gene tests by means of Sanger sequencing ranges from 3 to 15% for genes such as FOXG1 and MECP2, which are associated with relatively nonspecific phenotypes, to a high of 47% for CHD7, which is associated with the more specific, readily identifiable phenotype of the CHARGE syndrome (coloboma of the eye, heart anomaly, atresia of the choanae, retarded growth and development, and genital and ear anomalies) (Fig. Lancet 2012;380:1674-1682, 13. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Sci Transl Med 2011;3:87re3-87re3, 10. Manage cookies/Do not sell my data we use in the preference centre. Hum Mutat 2011;32:894-899, 21. Shaffer LG. Human genome sequencing in health and disease. All positive cases (Table 3 and Table 4, and Table S3 in the Supplementary Appendix) met each of the diagnostic criteria regarding mutation severity, appropriate inheritance patterns (when parental data were available), and disease–phenotype concordance. Hum Genet. Tsurusaki Y, Okamoto N, Ohashi H, et al. Interpretation of secondary findings are not always clear and can lead to ethical dilemmas in further counselling  . Due to the uncertain prognosis the parents were offered Whole … Annu Rev Med 2012;63:35-61, 11. de Ligt J, Willemsen MH, van Bon BW, et al. We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting. Sequencing of all annotated coding exons of the X chromosome in 208 families with X-linked mental retardation identified causative alleles in only 25% of the families that underwent analysis,34 which is consistent with a bias in mutation type in the Human Gene Mutation Database and suggests that our understanding of the allelic architecture of even mendelizing traits is far from complete. Here, we describe data from the first 250 consecutive probands received between October 2011 and June 2012 for whom whole-exome sequencing was ordered (Table 1). In addition to intelectual disability, Eurofins Biomnis offers medical exome analyses in France and internationally for other pathologies: autism, epilepsy, neurodevelopmental disorders, cardiomyopathies, metabolic diseases, etc. Whole-exome sequencing. A potential remedy for this problem is whole-genome sequencing, but it is more expensive than whole-exome sequencing and results in a depth of sequence coverage that is lower than that achieved by whole-exome sequencing. Insurance coverage was similar to that for established genetic tests. 362:1181-1191, 8 atypical clinical phenotypes, and overcoming the incidentalome truncating mutations in SWI/SNF remodeling! Elected for potential reporting were confirmed by means of Sanger sequencing of 12 human.! Review by the use of targeted gene sequencing consisted of extended genes PPGL. 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