Instituto da Crianca (Children's Hospital), Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Fleury Medicina e Saúde, São Paulo, Brazil.
Am J Med Genet C Semin Med Genet. 2021 Sep;187(3):364-372. doi: 10.1002/ajmg.c.31932. Epub 2021 Jul 16.
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 ) 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.
几种孟德尔疾病遵循常染色体隐性遗传模式。许多遗传性疾病的流行病学信息可能有助于指导罕见疾病的卫生政策,但这些信息往往是不充分的,尤其是在发展中国家。我们旨在使用外显子组测序 (WES) 计算巴西患者队列中罕见常染色体隐性孟德尔疾病的携带者频率。我们回顾了 320 名有隐性疾病携带者的症状患者的 WES 分子发现。使用 Hardy-Weinberg 方程,我们根据我们研究中观察到的各自携带者频率 (2pq) 估计隐性疾病频率 (q)。我们根据巴西提供这些检测的五个不同临床实验室的基因列表计算了携带者筛查测试的灵敏度。在 230 名患者的 278 个不同基因中报告了 425 个 351 个罕见变异的发生,其中近一半(48.8%)为至少一种罕见代谢疾病的杂合致病性/可能致病性变异的携带者,而 25.9%的患者患有癫痫,18.1%的患者患有智力障碍,15.6%的患者患有骨骼疾病,10.9%的患者患有免疫障碍,9.1%的患者患有听力损失。我们估计,平均有 67%的变异无法通过携带者筛查面板检测到。常染色体隐性疾病的合并频率估计为 26.39/10000(或~0.26%)。这项研究表明 WES 确定携带者状态的潜在研究效用,这可能是一种在人群水平评估隐性疾病的临床和社会负担并指导携带者筛查面板优化的可能策略。