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

• Published in: American journal of medical genetics. Part C, Seminars in medical genetics Vol. 187; no. 3; pp. 364 - 372
• Main Authors: Quaio, Caio Robledo D'Angioli Costa, Chung, Christine Hsiaoyun, Perazzio, Sandro Felix, Dutra, Aurelio Pimenta, Moreira, Caroline Monaco, Filho, Gil Monteiro Novo, Sacramento‐Bobotis, Patricia Rossi, Penna, Michele Groenner, Souza, Rafaela Rogerio Floriano, Cintra, Vivian Pedigone, Carnavalli, Juliana Emilia Prior, Silva, Rafael Alves, Paixão, Daniele, Baratela, Wagner Antonio da Rosa, Olivati, Caroline, Spolador, Gustavo Marquezani, Santos, Monize Nakamoto Provisor, Pintao, Maria Carolina, Fornari, Alexandre Ricardo dos Santos, Burger, Matheus, Ramalho, Rodrigo Fernandes, Pereira, Otavio Jose Eulalio, Ferreira, Elisa Napolitano, Mitne‐Neto, Miguel, Kim, Chong Ae
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.09.2021; Wiley Subscription Services, Inc
• Subjects: Autosomal recessive inheritance; carrier; Carrier frequencies; carrier frequency; Developing countries; Disabilities; Epidemiology; Epilepsy; Genes; Genetic screening; Genetics; Health policy; Hearing loss; Hereditary diseases; Heredity; Intellectual disabilities; LDCs; Mathematical analysis; Metabolic disorders; next‐generation sequencing; Optimization; Panels; Patients; Rare diseases; recessive Mendelian diseases; whole exome sequencing; Brazil
• ISSN: 1552-4868; 1552-4876
• DOI: 10.1002/ajmg.c.31932

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 (q2) 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.