Prevalence of the most common pathogenic variants in three genes for inborn errors of metabolism associated with sudden unexpected death in infancy: a population-based study in south Brazil

Abstract Citrullinemia type 1 (CTLNI), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), and mut0 methylmalonic acidemia (mut0 MMA) are inborn errors of metabolism (IEMs) associated with sudden unexpected death in infancy (SUDI). Its most common pathogenic variants are: c.1168G>A (CTLNI, ASS1 gene), c.1528G>C (LCHADD, HADHA gene), c.655A>T and c.1106G>A (mut0 MMA, MUT gene). Considering the absence of estimates regarding the incidence of these diseases in Brazil, this study sought to investigate the prevalence of its main pathogenic variants in a healthy population in the southern region of the country. A total of 1,000 healthy subjects from Rio Grande do Sul were included. Genotyping was performed by real-time PCR. Individuals found to be heterozygous for c.1528G>C underwent further acylcarnitine profile analysis by tandem mass spectrophotometry. Allele and genotype frequencies were calculated considering Hardy-Weinberg equilibrium. The c.1528G>C variant was detected in heterozygosity in two subjects (carrier frequency = 1:500; allele frequency = 0.001; minimum prevalence of LCHADD = 1: 1,000,000), whose acylcarnitine profiles were normal. Variants c.1168G>A, c.655A>T, and c.1106G>A were not identified. These results denote the rarity of these IEMs in Southern Brazil, highlighting the need to expand the investigation of IEMs in relation to infant morbidity and mortality within the country.摘要：1型瓜氨酸血症（Citrullinemia type 1, CTLNI）、长链3-羟酰基辅酶A脱氢酶缺乏症（long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, LCHADD）以及mut0型甲基丙二酸血症（mut0 methylmalonic acidemia, mut0 MMA）均为与婴儿猝死（sudden unexpected death in infancy, SUDI）相关的遗传代谢病（inborn errors of metabolism, IEMs）。此类疾病最常见的致病变异位点包括：c.1168G>A（对应CTLNI的ASS1基因）、c.1528G>C（对应LCHADD的HADHA基因）、c.655A>T与c.1106G>A（对应mut0 MMA的MUT基因）。鉴于目前尚无巴西境内上述疾病发病率的相关统计数据，本研究旨在探究该国南部地区健康人群中这些疾病主要致病变异位点的携带率。本研究共纳入来自南里奥格兰德州的1000名健康受试者，采用实时荧光定量PCR（real-time PCR）完成基因分型；针对检出c.1528G>C杂合变异的受试者，进一步采用串联质谱法开展酰基肉碱谱分析。基于哈迪-温伯格平衡（Hardy-Weinberg equilibrium）计算等位基因频率与基因型频率。结果显示，共在2名受试者中检出c.1528G>C杂合变异（携带者频率为1:500；等位基因频率为0.001；LCHADD最低患病率为1:1000000），两名受试者的酰基肉碱谱均正常；未检出c.1168G>A、c.655A>T与c.1106G>A这三类变异位点。上述研究结果表明，此类遗传代谢病在巴西南部地区较为罕见，同时凸显了在巴西境内拓展针对婴儿发病与死亡相关遗传代谢病研究的必要性。