Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases
Caio Robledo D’Angioli Costa Quaio, Caroline Mônaco Moreira, Gil Monteiro Novo‐Filho, Patricia Rossi Sacramento‐Bobotis, Michele Groenner Penna, Sandro Félix Perazzio, Aurélio Pimenta Dutra, Rafael Alves da Silva, Monize Nakamoto Provisor Santos, Vanessa Yurie Nozaki de Arruda, Vanessa Galdeno Freitas, Vinícius Ceola Pereira, Maria Carolina Tostes Pintão, Alexandre Ricardo dos Santos Fornari, Ana Lígia Buzolin, Andre Yuji Oku, Matheus Carvalho Bürger, Rodrigo Fernandes Ramalho, David Santos Marco Antônio, Elisa Napolitano Ferreira, Otavio Jose Eulalio Pereira, Vanessa Dionisio Cantagalli, Ana Carolina Gomes Trindade, Rafaela Rogerio Floriano de Sousa, Cintia Reys Furuzawa, Fernanda Verzini, Shirley Dezan Matalhana, Naiade Romano, Daniele Paixão, Caroline Olivati, Gustavo Marquezani Spolador, Gustavo Arantes Rosa Maciel, Viviane Zorzanelli Rocha, Javier Miguelez, Mário Henrique Burlacchini de Carvalho, Alexandre Wagner Silva de Souza, Luís Eduardo Coelho Andrade, Maria de Lourdes Chauffaille, Aline dos Santos Borgo Perazzio, Ana Lúcia Pereira Monteiro Catelani, Miguel Mitne‐Neto, Chong Ae Kim, Wagner Antonio da Rosa Baratela
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.