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. 2020 Dec;184(4):955-964.
doi: 10.1002/ajmg.c.31860. Epub 2020 Nov 30.

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

Caio Robledo D'Angioli Costa Quaio  1   2 , Caroline Monaco Moreira  1 , Gil Monteiro Novo-Filho  1 , Patricia Rossi Sacramento-Bobotis  1 , Michele Groenner Penna  1 , Sandro Felix Perazzio  1   3 , Aurelio Pimenta Dutra  1 , Rafael Alves da Silva  1   4 , Monize Nakamoto Provisor Santos  1 , Vanessa Yurie Nozaki de Arruda  1 , Vanessa Galdeno Freitas  1   5 , Vinícius Ceola Pereira  1 , Maria Carolina Pintao  1 , Alexandre Ricardo Dos Santos Fornari  1 , Ana Lígia Buzolin  1 , Andre Yuji Oku  1 , Matheus Burger  1 , Rodrigo Fernandes Ramalho  1 , David Santos Marco Antonio  1 , Elisa Napolitano E Ferreira  1 , Otavio Jose Eulalio Pereira  1 , Vanessa Dionisio Cantagalli  1 , Ana Carolina Gomes Trindade  1 , Rafaela Rogerio Floriano de Sousa  1 , Cintia Reys Furuzawa  1 , Fernanda Verzini  1 , Shirley Dezan Matalhana  1 , Naiade Romano  1 , Daniele Paixão  1 , Caroline Olivati  1 , Gustavo Marquezani Spolador  1 , Gustavo Arantes Rosa Maciel  1   6 , Viviane Zorzanelli Rocha  1   7 , Javier Miguelez  1 , Mario Henrique Burlacchini de Carvalho  1   8 , Alexandre Wagner Silva de Souza  1   3 , Luis Eduardo Coelho Andrade  1   3 , Maria de Lourdes Chauffaille  1 , Aline Dos Santos Borgo Perazzio  1 , Ana Lucia Pereira Monteiro Catelani  1 , Miguel Mitne-Neto  1 , Chong Ae Kim  2 , Wagner Antonio da Rosa Baratela  1
Affiliations

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

Caio Robledo D'Angioli Costa Quaio et al. Am J Med Genet C Semin Med Genet. 2020 Dec.

Abstract

Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.

Keywords: diagnostic yield; exome sequencing; incidental findings; rare diseases; secondary findings.

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