Abstract

The aim of the study was to develop a panel for detecting heterozygous carriage of frequent mutations associated with phenylketonuria (PKU), and to determine their allelic frequencies in one of the regions of Russia. PKU is one of the most common monogenic diseases with autosomal recessive inheritance. Carrier screening leads to a reduction in the number of children born with PKU. The diagnostic panel included 23 pathogenic variants of the PAH gene nucleotide sequence. Participants of the study (n = 642) were randomly selected from an ESSE-Vologda population-based study. Genotyping was performed using real-time polymerase chain reaction on a QuantStudio 12K Flex Real-Time PCR System (Thermo Fisher Scientific, United States). The data were analyzed using the TaqMan Genotyper Software (Thermo Fisher Scientific, United States). Seventeen heterozygous carriers of six variants of the nucleotide sequence associated with the development of PKU were identified: R408W (rs5030858), A403V (rs5030857), I306V (rs62642934), L48S (rs5030841), IVS12+1G>A (rs5030861), R261Q (rs5030849_C_T). The frequency of heterogyzotes in the Russian population was 2.65% (95% CI 1.55–4.21), or 1 : 38. The data obtained indicate the prospects of mass screening for the carriage of frequent mutations associated with PKU in people with an uncomplicated family history. The developed diagnostic panel allows one to rapidly obtain the result of genetic analysis and can be used for PKU carrier screening.

中文翻译：

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在基于 ESSE-Vologda 人群的队列研究中，与苯丙酮尿症发展相关的 PAH 基因核苷酸序列变体的杂合携带频率

摘要

该研究的目的是开发一个用于检测与苯丙酮尿症 (PKU) 相关的频繁突变的杂合子携带的面板，并确定它们在俄罗斯一个地区的等位基因频率。PKU 是最常见的单基因疾病之一，具有常染色体隐性遗传。携带者筛查可减少 PKU 出生的儿童数量。诊断面板包括PAH基因核苷酸序列的23 个致病变异。研究参与者 ( n= 642) 是从 ESSE-Vologda 基于人群的研究中随机选择的。在 QuantStudio 12K Flex 实时 PCR 系统（Thermo Fisher Scientific，美国）上使用实时聚合酶链反应进行基因分型。使用 TaqMan Genotyper 软件（Thermo Fisher Scientific，美国）分析数据。鉴定了与 PKU 发展相关的核苷酸序列的六种变体的 17 个杂合携带者：R408W (rs5030858)、A403V (rs5030857)、I306V (rs62642934)、L48S (rs5030841)、IVS12+510G>2 rs5030849_C_T)。俄罗斯人群中杂合子的频率为 2.65% (95% CI 1.55–4.21)，或 1:38。获得的数据表明，在没有复杂家族史的人群中，对携带与 PKU 相关的频繁突变进行大规模筛查的前景.