Caio Robledo D' Angioli Costa Quaio1,2,3,4, Caroline Monaco Moreira5, Christine Hsiaoyun Chung5, Sandro Felix Perazzio5,6, Aurelio Pimenta Dutra5, Chong Ae Kim7. 1. Instituto da Criança (Children's Hospital), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil. cquaio@gmail.com. 2. Fleury Medicina e Saúde, São Paulo, SP, Brazil. cquaio@gmail.com. 3. Laboratório Clínico, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil. cquaio@gmail.com. 4. Instituto da Criança do Hospital das Clínicas da FMUSP - Unidade de Genética, Av. Dr. Enéas Carvalho de Aguiar, 647. Cerqueira César, São Paulo, SP, CEP 05403-900, Brazil. cquaio@gmail.com. 5. Fleury Medicina e Saúde, São Paulo, SP, Brazil. 6. Division of Rheumatology, Universidade Federal de São Paulo, São Paulo, SP, Brazil. 7. Instituto da Criança (Children's Hospital), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
Abstract
BACKGROUND: Several metabolic disorders follow an autosomal recessive inheritance pattern. Epidemiological information on these disorders is usually limited in developing countries. Our objective is to assess carrier frequencies of rare autosomal recessive metabolic diseases in a cohort of Brazilian patients that underwent molecular investigation with exome sequencing and estimate the overall frequency of these diseases using the Hardy-Weinberg equation. METHODS AND RESULTS: We reviewed the molecular findings of 320 symptomatic patients who had carrier status for recessive diseases actively searched. A total of 205 rare variants were reported in 138 different genes associated with metabolic diseases from 156 patients, which represents that almost half (48.8%) of the patients were carriers of at least one heterozygous pathogenic/likely pathogenic (P/LP) variant for rare metabolic disorders. Most of these variants are harbored by genes associated with multisystemic involvement. We estimated the overall frequency for rare recessive metabolic diseases to be 10.96/10,000 people, while the frequency of metabolic diseases potentially identified by newborn screening was estimated to be 2.93/10,000. CONCLUSIONS: This study shows the potential research utility of exome sequencing to determine carrier status for rare metabolic diseases, which may be a possible strategy to evaluate the clinical and social burden of these conditions at the population level and guide the optimization of health policies and newborn screening programs.
BACKGROUND: Several metabolic disorders follow an autosomal recessive inheritance pattern. Epidemiological information on these disorders is usually limited in developing countries. Our objective is to assess carrier frequencies of rare autosomal recessive metabolic diseases in a cohort of Brazilian patients that underwent molecular investigation with exome sequencing and estimate the overall frequency of these diseases using the Hardy-Weinberg equation. METHODS AND RESULTS: We reviewed the molecular findings of 320 symptomatic patients who had carrier status for recessive diseases actively searched. A total of 205 rare variants were reported in 138 different genes associated with metabolic diseases from 156 patients, which represents that almost half (48.8%) of the patients were carriers of at least one heterozygous pathogenic/likely pathogenic (P/LP) variant for rare metabolic disorders. Most of these variants are harbored by genes associated with multisystemic involvement. We estimated the overall frequency for rare recessive metabolic diseases to be 10.96/10,000 people, while the frequency of metabolic diseases potentially identified by newborn screening was estimated to be 2.93/10,000. CONCLUSIONS: This study shows the potential research utility of exome sequencing to determine carrier status for rare metabolic diseases, which may be a possible strategy to evaluate the clinical and social burden of these conditions at the population level and guide the optimization of health policies and newborn screening programs.