Tier one was focused on the disease phenotype and included deleterious mutations and variants of unknown clinical significance related to the phenotype. One of the concerns raised by the use of WES is the potential for secondary findings. https://decipher.sanger.ac.uk/browser#q/FAM111A/location/11:58791366-59041366. Nat Genet 2009;41:535-543, 35. The postnatal 3D CT scan confirmed the skeletal abnormalities that were detected in the prenatal ultrasound. 2019 have confirmed the diagnostic potential of prenatal exome sequencing [6, 7]. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. In addition, 4 patients received molecular diagnoses of two nonoverlapping genetic disorders: 3 with both an autosomal dominant disorder and an autosomal recessive disorder and 1 with an autosomal recessive disorder and an X-linked disorder (Table 4). Genome Med 2009;1:13-13, 18. The introduction of rapid targeted exome sequencing with results available within 3 weeks allows for prenatal management. Nature 2010;467:1061-1073, 19. Vissers LE, de Ligt J, Gilissen C, et al. - Exome Sequencing interesting case discussions - Guidelines and Recommendations Outline. Interpretation of secondary findings are not always clear and can lead to ethical dilemmas in further counselling [9] . Next Generation Sequencing in Molecular Diagnosis A powerful tool for gene discovery 200 genes are discovered every year Now a powerful diagnostic tool ! Horn R, Parker M. Opening Pandora's box? Analysis and interpretation of the exome data has been too slow to be helpful in the prenatal setting, which requires rapid results. Hum Mutat 2010;31:1326-1342, 5. The testing and analysis were performed at the Baylor College of Medicine in clinical diagnostic laboratories certified by CAP and CLIA. Whole exome sequencing has become a useful diagnostic aid for genetic disorders including multigene dermatoses such as epidermolysis bullosa 5, 6 and acrokeratosis verruciformis 7. OCS is allelic to the less severe Kenny Caffey syndrome (KCS), which is also characterised by impaired skeletal development with small, thin skeletal bones, increased bone density and hypocalcaemia. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. The Human Gene Mutation Database: 2008 update. For each of the 62 cases, a claim of causality depended on the referring physician's agreement with the molecular diagnosis. Kohane IS, Hsing M, Kong SW. Taxonomizing, sizing, and overcoming the incidentalome. Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case Gabrielle Bradshaw , Robbie R. Lualhati , Cassie L. Albury , Neven … Am J Hum Genet 2010;86:749-764, 31. The 20-week ultrasound scan identified shortened long bones and an unusual skull shape (Fig. Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Exome Sequencing, a genetic test that analyzes the coding portion of a person’s genome, often provides a diagnosis in cases where previous testing has not. This limits analysis to those genes that have mutations compatible with the phenotype identified on ultrasound. Samples were available from both parents for 75% of the patients. The standard of practice involves the recognition of specific phenotypic or radiographic features or biopsy findings in addition to the analysis of metabolites, genomic tests such as karyotyping or array-based comparative genomic hybridization,3,4 or the selection of candidate-gene tests, including single-gene analyses and gene-panel tests. Best S, Wou K, Vora N, , Van der Veyver I, Wapner R. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Information, resources, and support needed to approach rotations - and life as a resident. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. The remaining 14% were found to be false positive results; these calls usually had unequal allele fractions, poor mapping scores, or sequence data indicating suboptimal alignment to the reference sequence. The costs of testing were billed to the insurance company by the Baylor College of Medicine laboratory for 129 cases (52%), 3 of which were denied coverage; 119 (48%) were billed to the referring institution, and 2 (1%) were nonbilled cases. Cookies policy. 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. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. AJHG. N Engl J Med 2009;360:599-605, 32. Case report: targeted whole exome sequencing enables the first prenatal diagnosis of the lethal skeletal dysplasia Osteocraniostenosis. An exome sequencing approach in these patients provides a balance between cost and benefit, allowing for all disease-causing genes to be analysed simultaneously and therefore reducing … We suggest that as testing with whole-exome sequencing evolves to characterize more patients with atypical presentations of known genetic diseases, the spectrum of phenotypes associated with genetic disorders will expand. A 78 years old Chinese woman with five different cancer types and a family history of malignancy was the subject of this study. 2). Of the 36 dominant alleles, 24 (67%) were novel variants at the time of diagnosis. In the first 14 cases sequencing was initially performed on fetal DNA only. Genet Med 2008;10:294-300, 20. Genetic sequencing is expected to greatly improve the rate of diagnoses for rare conditions in the future. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Home » Sponsors » Genomics: Clinical Implementation » Unexplained Liver Disease Cases Diagnosed by Exome Sequencing. Tarpey PS, Smith R, Pleasance E, et al. Confirmed variants were required to have occurred in genes in which mutations had been previously reported to cause disease with a presentation consistent with that observed in the patient. Exome Sequencing (ES) refers to the capture and sequencing of the coding fraction of the genome. Correspondence to 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). On the basis of the charges listed for these tests, we found that the cost of this patient's previous genetic testing was three times as high as the current cost of whole-exome sequencing. A map of human genome variation from population-scale sequencing. Annu Rev Med 2010;61:437-455, 33. View 0 peer reviews of Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate on Publons Download Web of Science™ My Research Assistant : Bring the power of the Web of Science to … An exome sequencing approach in these patients provides a balance between cost and benefit, allowing for all disease-causing genes to be analysed simultaneously and therefore reducing the need for sequential testing whilst optimizing diagnostic yield. Overall, exome sequencing yielded a definitive diagnosis in five of the 24 cases tested (21%), a highly plausible diagnosis in one further fetus and was highly suggestive of an … We also requested a recent clinic note summarizing the case and the prior workup. ), Baylor College of Medicine, Houston. 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. Despite advances in ultrasound, accurate prenatal diagnosis is limited to those syndromes with a characteristic phenotype such as thanatophoric dysplasia and achondroplasia. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Part of For WES to be used successfully, good phenotyping is essential. Genome Med 2013;5:57-57. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited. Lancet 2012;380:1674-1682, 13. NEW YORK (GenomeWeb) – New research suggests that exome sequencing can unearth diagnostically relevant mutations in a subset of adults with unexplained liver disease. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine, A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. This demonstrates that, when the prognosis of a fetus is uncertain, the prenatal targeted WES could be used as a tool to help with management and treatment decisions. 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. TH, a clinical geneticist analysed the data and confirmed phenotype genotype correlation. Structural variation in the human genome and its role in disease. Stankiewicz P, Lupski JR. (Fig. This study describes the first prenatal diagnosis of OCS. PubMed Google Scholar. Results Among the 76 cases with an indication of CDH+, a molecular diagnosis … Valuable tools for building a rewarding career in health care. This group included 33 patients with autosomal dominant disease, 16 with autosomal recessive disease, and 9 with X-linked disease. The possibility of false positive results exists but is small and similar to that for other laboratory diagnoses that need to be considered in the context of the clinical presentation. Approximately 1–2% of the human genome encodes the exome but it is thought to contain more than 85% of all disease causing mutations [5]. For example, 7 patients, including those with mutations in ARID1A, ARID1B (in 2 patients), KANSL1, SMARCB1, SRCAP, and C5orf42, would not have received a diagnosis if this study had been conducted before 2012, when certain study reports became available. Tidyman WE, Rauen KA. Among the 500 additional clinical exomes completed during the review process for this article, we obtained a similar diagnostic yield, at 26% (data not shown). 1994;31(10):772–778. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. (Funded by the National Human Genome Research Institute.). Molecular Diagnoses in Mendelian Diseases in 62 Positive Cases. In conclusion, the use of whole-exome sequencing to analyze 250 consecutive clinical cases yielded a diagnosis in 25% of these cases, which supports the use of whole-exome sequencing as a diagnostic test for patients with nonspecific or unusual disease presentations of possible genetic cause and for patients with clinical diagnoses of heterogeneous genetic conditions. 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. For the 20 patients with autosomal recessive disease (including the 4 patients with two nonoverlapping genetic disorders), parental studies indicated that 19 had inherited mutant alleles from each carrier parent. Previous studies have shown that 31% of patients with nonsyndromic, sporadic cases of intellectual disability (16 of 51 patients) and 13% of those with severe intellectual disability (13 of 100) can be provided with a specific molecular diagnosis by means of next-generation sequencing approaches.11,12 The 25% diagnostic rate in our clinical study may be the result of different categories of presentation; 200 of 250 patients had intellectual disability as one of the clinical features, and the diagnosis was determined in 51 of these patients (26%) by means of whole-exome sequencing. Global report on birth defects: the hidden toll of dying and disabled children. LP was the main author writing the manuscript. 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. 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. DNA from macrodissected, formalin-fixed paraffin-embedded tumor and PBMCs was captured using Agilent SureSelect Clinical Research Exome kits (Agilent) and sequenced on Illumina NextSeq 500 sequencers (Illumina) according to the manufacturers’ instructions. Whole exome sequencing … Nonimmune hydrops fetalis (NIHF), a fetal … Here, we describe the first prenatal diagnosis of OCS. Rauch A, Wieczorek D, Graf E, et al. Genome Res 2010;20:273-280, 17. Nature 2009;461:272-276, 7. Only the 1000 most recent citing articles are listed here. Lancet. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. 2018;38(1):20–5. Four Patients with Dual Molecular Diagnoses. Whole exome sequencing identified 20 mutation sites in six candidate genes. A short clinical synopsis was constructed by the laboratory clinical geneticist and was included in the final report for review by the referring physician. 6 The mean molecular diagnostic yield of exome sequencing … 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. Peripheral-blood samples were provided in most cases, although other sources of DNA were accepted and samples from both parents were usually provided. Ng SB, Turner EH, Robertson PD, et al. White Plains, NY: March of Dimes Birth Defects Foundation, 2006. Shen Y, Wan Z, Coarfa C, et al. The majority of cases reported thus far have only reported the results after the pregnancy [8]. Previously, diagnosis has only been possible postnatally on clinical and radiological features. A cloverleaf skull is often associated with OCS. The diagnoses in approximately 25% of our 62 patients with positive cases were based on disease-gene discoveries made within the past 2 years, which suggests that most of the genes that underlie mendelian diseases have yet to be discovered. statement and Clinical Exome sequencing is a highly complex molecular test that analyzes the exons (or coding regions) of thousands of genes from a small sample of blood, by next generation sequencing … Bioinformatics 2009;25:1754-1760, 16. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Additional information from family studies or further feedback from referring physicians may also establish more diagnoses among the cases in our study that have not yet been identified through whole-exome sequencing. More than half of the patients remain Gahl WA, Markello TC, Toro C, et al. Having a diagnosis can bring an end to the costly and emotionally draining diagnostic … Of 146 total cases, 46 received a molecular diagnosis from exome sequencing, an overall diagnostic rate of 32% (Table 1). The other three patients presented with atypical clinical phenotypes, and Noonan-spectrum disorders were not in the immediate differential diagnosis. This mutation had previously been detected in two cases and was lethal in both perinatally. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. This provided essential prognostic information and allowed parental choice regarding further pregnancy management. We used targeted WES to achieve the first reported case of a prenatal diagnosis of OCS. Methods We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions. Whole-exome sequencing (WES) yields a diagnosis of the underlying genetic cause in 25–35% of children with an unexplained presumed genetic disorder (such as a birth defect) after negative … NEW! Apr 15, 2019 | staff reporter. VR and AH performed the whole exome sequencing. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. All authors read and approved the final manuscript. Each patient (and their parents or guardians, as appropriate) was advised of the potential disclosure of medically actionable incidental findings, defined as conditions unrelated to the indication for testing that might warrant treatment or additional medical surveillance for the patient and possibly other family members. © 2021 BioMed Central Ltd unless otherwise stated. Genet Med 2005;7:650-654, 30. Nikkel SM, Ahmed A, Smith A, Marcardier J. Mother-to-daughter transmission of Kenny–Caffey syndrome associated with the recurrent, dominant FAM111A mutation p.Arg569His. In contrast to whole-genome sequencing, which analyzes the 3 billion base pairs in the human genome, whole-exome sequencing … Gains will be made through improved detection of copy-number variation; such genomic changes contribute substantively to disease burden,32 but not all are detected by current array-comparative genomic hybridization testing. There is also the possibility of an evolving phenotype that might at some point alter or add to the diagnosis in some patients. Furthermore, a delayed diagnosis may have a significant impact on the patient’s treatment and quality of life. … The 86 mutations included a full range of mutation types: 20 small frameshift, 2 in-frame, 9 nonsense, 9 splice, and 46 missense mutations. Diagnostic exome sequencing in persons with severe intellectual disability. Objective To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Clinical Description of Patients for Whom Whole-Exome Sequencing Was Ordered. Hoyer J, Ekici AB, Endele S, et al. Briefly, genomic DNA samples from probands were fragmented with the use of sonication, ligated to Illumina multiplexing paired-end adapters, amplified by means of a polymerase-chain-reaction assay with the use of primers with sequencing barcodes (indexes), and hybridized to biotin-labeled VCRome, version 2.1,14 a solution-based exome capture reagent that was designed in-house and is commercially available (Roche NimbleGen). The researchers searched for CDH+ patients in a clinical database of approximately 12,000 individuals referred to Baylor Genetics for exome sequencing. Curr Opin Genet Dev 2009;19:230-236, 23. Clin Genet. Many patients with genetic diseases are not given a specific diagnosis. Lupski JR, Gonzaga-Jauregui C, Yang Y, et al. Targeted capture and massively parallel sequencing of 12 human exomes. By using this website, you agree to our 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%. Patients presented with a range of phenotypes suggesting potential genetic causes. Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. Laboratory coordinators monitored the submission of these forms and ensured receipt before interpretation of the data from whole-exome sequencing. : Clinical whole-exome sequencing for the diagnosis of mendelian disorders. Our case proves that next-generation sequencing is an effective method for the rapid diagnosis and determination of XP genetic etiology. The authorized source of trusted medical research and education for the Chinese-language medical community. However, it is uncertain whether the use of Whole Exome Sequencing (WES) represents a more effective approach for diagnosis of cases with HCM and DCM. Abstract Whole-exome sequencing is increasingly used for diagnosis and identification of appropriate therapies in patients. Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. If a 2nd trimester ultrasound is performed at 20–22 weeks gestation and the WES results take 3 weeks, then the prenatal choices may be limited for couples who live in countries with more stringent pregnancy termination laws. Technical limitations may also account for a small but considerable fraction of cases in which whole-exome sequencing did not identify the variation underlying an apparent mendelian disorder. Background Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder resulting from deficiency in base excision repair caused by single-nucleotide mutations, especially in skin exposed to sunlight ( Okamura et al., 2015 ). A 78 years old Chinese woman with five different cancer types and a family history of malignancy was the subject of this study. The couple were counselled about the uncertainty of the child’s prognosis and offered targeted whole exome sequencing (WES). NEW YORK – Exome sequencing can lead to a molecular diagnosis in 10 percent to 33 percent of people with cerebral palsy, a new analysis from researchers at Geisinger and … Information and tools for librarians about site license offerings. Insurance coverage was similar to that of established genetic tests. It can be useful in identifying patients who would benefit from targeted therapies, such as vasopressin 2 antagonists in the case … The TAT is 6 weeks from sample receipt for a negative result, however, it may be extended if specific confirmations are required. Nat Genet 2012;44:379-380, 26. S1 in the Supplementary Appendix). N Engl J Med 2010;362:1181-1191, 8. Sci Transl Med 2011;3:87re3-87re3, 10. Chandler N, Best S, Hayward J, Faravelli F, Mansour S, Kivuva E, Tapon D. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. The mutant alleles may be located in the coding regions that are not well covered by whole-exome sequencing (about 5% of the coding regions) (Table S1 in the Supplementary Appendix). 1. The prior diagnostic workup of all 15 positive cases from local referrals is shown in Table S2 in the Supplementary Appendix. However, it is uncertain whether the use of Whole Exome Sequencing (WES) represents a more effective approach for diagnosis of cases with HCM and DCM. A subsequent ultrasound scan confirmed an unusual skull shape; however the features were not consistent with a typical cloverleaf skull. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. 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. American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation. Richards CS, Bale S, Bellissimo DB, et al. Gonzaga-Jauregui C, Lupski JR, Gibbs RA. It is likely that as whole-exome sequencing and whole-genome sequencing achieve more widespread clinical implementation, multiple “hits” in a patient that explain the superimposed traits or blended phenotypes will become more commonplace. 2013;86(4):394–5. RB analysed and interpreted the patient’s CT scans. Previously, OCS has only been diagnosed postnatally with a combination of typical dysmorphic features, presence of hypocalcaemia and radiological features [3]. Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Verloes A, Narcy F, Guibaud P, Schaaps J, Le Merrer M, Marot M. Osetocraniostenosis. The 105 fetal and 209 matched parental samples (including 104 trio families and one fetus-parent dyad) were analyzed by medical exome sequencing … Inheritance Pattern and Medical Presentation of Patients with Established Molecular Diagnosis. GM 1-gangliosidosis had previously been excluded from consideration, but was subsequently identified as the correct diagnosis using exome sequencing. We thank the patients and their families for participating in this study and their physicians for submitting the clinical samples; Eric Boerwinkle, Ph.D., for expert advice and collaboration; Alicia Hawes, Mark Scheel, Nehad Saada, Wendy Liu, Irene Miloslavskaya, and Wenmiao Zhu for expert technical and bioinformatics development and support; Linda Guynn for patient-chart review; and Jeffrey Mize, Sean Kim, Doreen Ng, and Michelle Rives for administrative program support. Briefly, the output data from the Illumina Genome Analyzer IIx or HiSeq 2000 were converted from a bcl file to a FastQ file by means of Illumina Consensus Assessment of Sequence and Variation software, version 1.8, and mapped to the reference haploid human-genome sequence (Genome Reference Consortium human genome build 37, human genome 19) with the use of the BWA program.15 Variant calls, which differed from the reference sequence, were obtained with the use of Atlas-SNP and Atlas-indel.16 Another in-house software program, CASSANDRA, was used for variant filtering and annotation (see the Supplementary Appendix). 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). Boone PM, Bacino CA, Shaw CA, et al. The aggregate, deidentified reporting of these data was approved by the local institutional review board without the need for further informed consent. WES is a powerful tool for accurate prenatal diagnosis, but it must be done after the 2nd trimester ultrasound. Exome sequencing … De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Scientists with doctorates and expertise in genetics or genomics, clinical molecular geneticists and medical geneticists certified by the American Board of Medical Genetics, medical directors, and genetic counselors performed several independent levels of review. He had previously been evaluated by means of chromosomal microarray analysis, DNA methylation, eight single-gene sequencing tests, mitochondrial genome sequencing by next-generation sequencing, respiratory-chain enzyme analysis, and multiple biochemical analyte studies. A total of 36 patients had autosomal dominant disorders (including 3 of the patients with two nonoverlapping genetic disorders); 6 (17%) of these patients, for whom parental data were not available, carried truncating mutations or missense mutations that had previously been reported in affected persons, 5 (14%) had inherited mutations from symptomatic parents, and 25 (69%; 83% of the 30 patients for whom parental data were available) had de novo mutations, including one de novo mutation in the mosaic state. 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. 2018;137(2):175–81. We applied stringent criteria for determining causative alleles. Miller DT, Adam MP, Aradhya S, et al. Most patients were younger than 18 years of age; four specimens from fetuses from terminated pregnancies were also included. 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