Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases

Quaio, Caio Robledo; Moreira, Caroline Monaco; Novo-Filho, Gil Monteiro; Sacramento-Bobotis, Patricia Rossi; Penna, Michele Groenner; Perazzio, Sandro Félix; Dutra, Aurelio Pimenta; Silva, Rafael Alves da; Santos, Monize Nakamoto Provisor; Arruda, Vanessa Y.N. de; Freitas, Vanessa Galdeno; Pereira, Vinícius Ceola; Pintão, Maria Carolina; Fornari, Alexandre Ricardo Dos Santos; Buzolin, Ana Lígia; Oku, Andre Yuji; Bürger, Matheus Carvalho; Ramalho, Rodrigo F.; Antônio, David Santos Marco; Ferreira, Elisa Napolitano; Pereira, Otavio Jose Eulalio; Cantagalli, Vanessa Dionisio; Trindade, Ana Carolina Gomes; Sousa, Rafaela Rogerio Floriano de; Furuzawa, Cintia Reys; Verzini, Fernanda; Matalhana, Shirley Dezan; Romano, Naiade; Paixão, Daniele; Olivati, Caroline; Spolador, Gustavo Marquezani; Maciel, Gustavo Arantes Rosa; Rocha, Viviane Z.; Miguelez, J.; Carvalho, Mário Henrique Burlacchini de; Souza, Alexandre Wagner Silva de; Andrade, Luís Eduardo Coelho; Chauffaille, Maria de Lourdes Lopes Ferrari; Perazzio, Aline Dos Santos Borgo; Catelani, Ana Lúcia; Mitne‐Neto, Miguel; Kim, Chong; Baratela, Wagner Antonio da Rosa

doi:10.1002/ajmg.c.31860

Cited by 25 publications

(34 citation statements)

References 25 publications

(49 reference statements)

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“… 19-case study, for inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [ 69 ]. 6-case study for inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [ 70 ]. 102-case study, because 15 fetuses were elected for multiple anomalies highly suggestive of a genetic disorder, while further enrollment was extended to each pregnancy with fetal anomaly [ 71 ].…”

Section: Resultsmentioning

confidence: 99%

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Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review

et al. 2021

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The introduction of Next Generation Sequencing (NGS) technologies has exerted a significant impact on prenatal diagnosis. Prenatal Exome Sequencing (pES) is performed with increasing frequency in fetuses with structural anomalies and negative chromosomal analysis. The actual diagnostic value varies extensively, and the role of incidental/secondary or inconclusive findings and negative results has not been fully ascertained. We performed a systematic literature review to evaluate the diagnostic yield, as well as inconclusive and negative-result rates of pES. Papers were divided in two groups. The former includes fetuses presenting structural anomalies, regardless the involved organ; the latter focuses on specific class anomalies. Available findings on non-informative or negative results were gathered as well. In the first group, the weighted average diagnostic yield resulted 19%, and inconclusive finding rate 12%. In the second group, the percentages were extremely variable due to differences in sample sizes and inclusion criteria, which constitute major determinants of pES efficiency. Diagnostic pES availability and its application have a pivotal role in prenatal diagnosis, though more homogeneity in access criteria and a consensus on clinical management of controversial information management is envisageable to reach widespread use in the near future.

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Section: Resultsmentioning

confidence: 99%

“…6-case study for inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [ 70 ].…”

Section: Resultsmentioning

confidence: 99%

Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review

et al. 2021

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“…These patients were selected from an original cohort of 500 symptomatic patients who had undergone molecular analysis for suspected diseases with genetic etiology from 2016 to 2020 in facilities of the Fleury Group. Full details of the clinical features of patients, molecular analysis, bioinformatics protocols, clinical data, and molecular data for primary and secondary findings were previously published (Quaio et al, 2020). A clinical summary is available in Data S1, Supporting Information (section "Case overview").…”

Section: Selection Of Cases Molecular Analysis and Bioinformaticsmentioning

confidence: 99%

Frequency of carriers for rare recessive Mendelian diseases in a Brazilian cohort of 320 patients

Quaio

Chung

Perazzio

et al. 2021

American J of Med Genetics Pt C

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Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES). We reviewed the molecular findings of WES from 320 symptomatic patients who had carrier status for recessive diseases. Using the Hardy-Weinberg equation, we estimated recessive disease frequencies (q 2 ) considering the respective carrier frequencies (2pq) observed in our study. We calculated the sensitivity of carrier screening tests based on lists of genes from five different clinical laboratories that offer them in Brazil. A total of 425 occurrences of 351 rare variants were reported in 278 different genes from 230 patients (71.9%). Almost half (48.8%) were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders, while 25.9% of epilepsy, 18.1% of intellectual disabilities, 15.6% of skeletal disorders, 10.9% immune disorders, and 9.1% of hearing loss. We estimated that an average of 67% of the variants would not have been detected by carrier screening panels. The combined frequencies of autosomal recessive diseases were estimated to be 26.39/10,000 (or $0.26%). This study shows the potential research utility of WES to determine carrier status, which may be a possible strategy to evaluate the clinical and social burden of recessive diseases at the population level and guide the optimization of carrier screening panels.

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“…First, a reinterpretation of variants of uncertain significance in a cohort of 341 individuals with neurogenetic disorders from Buenos Aires and Cincinnati during follow up showed a 30% reclassification to pathogenic variants (Salinas et al, 2020). In another study using exome analysis in 500 individuals from Brazil (Quaio et al, 2020), the authors provided a high diagnostic yield and therapeutic and management interventions tailored to specific diagnosis. In this study, there was a 7.4% rate of secondary findings using the ACMG reporting Skeletal dysplasias are a particular group of genetic diseases requiring specific expertise for the diagnosis.…”

Section: Introduction To the Special Issue On Clinical Genetics In Lamentioning

confidence: 99%

Introduction to the special issue on Clinical Genetics in Latin America

Prada

Cavalcanti

Schwartz

et al. 2020

American J of Med Genetics Pt C

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Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases

Cited by 25 publications

References 25 publications

Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review

Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review

Frequency of carriers for rare recessive Mendelian diseases in a Brazilian cohort of 320 patients

Introduction to the special issue on Clinical Genetics in Latin America

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