Pediatrics, Bozüyük State Hospital, Bilecik, Turkey.
Department of Paediatrics, Eskisehir Osmangazi University Faculty of Medicine, Division of Child Nutrition and Metabolism, Eskisehir, Turkey.
J Pediatr Endocrinol Metab. 2022 Mar 30;35(5):639-647. doi: 10.1515/jpem-2022-0047. Print 2022 May 25.
The aim of our study was to define the genotype-phenotype correlations of mutations in the gene among the Turkey's Central Anatolian region.
Demographic characteristics of 108 patients with hyperphenylalaninemia (HPA) and 94 patients whose diagnosis was confirmed by gene analysis (Sanger DNA Sequence Analysis and Next-Generation Sequencing) were determined retrospectively. Blood phenylalanine levels were analyzed using the high-performance liquid chromatography method.
Mild HPA-not-requiring-treatment (NT) was found in 50.9% of the patients, and a classical phenylketonuria (PKU) phenotype was found in 25.9%. Forty-seven types of variants were identified. The predominant variants were p.Ala403Val (9.9%), p.Ala300Ser (9.4%), and c.1066-11G>A (splicing) (9.4%). Missense mutations accounted for 68% of mutations and attenuated the clinical impact; splice variations were found in 14.8% of cases with severe features. The p.Thr380Met allele was specific to the mild HPA-NT group. The c.1066-11G>A (splicing) allele was associated with classical PKU, whereas the p.Arg408Trp allele was linked to severe symptoms. Three variations of unknown clinical significance were discovered: c.706+4A>T (splicing), c.843-5T>C (splicing), and p.Thr323=. Of these variants, the patient who was homozygous for the c.843-5T>C (splicing) allele related to the classical PKU phenotype. 70% of the patients who underwent tetrahydrobiopterin (BH4) test were responsive. Phenotypes that responded to BH4 treatment were mostly mild phenotypes.
The genotype is the main factor that determines the phenotype of PKU. Establishing the relationship between the identified genetic mutations and phenotypic characteristics will provide very important data for each patient in terms of the specific management style.
本研究旨在定义土耳其中安纳托利亚地区 基因突变的基因型-表型相关性。
回顾性分析 108 例高苯丙氨酸血症（HPA）患者和 94 例经基因分析（Sanger DNA 序列分析和下一代测序）确诊患者的人口统计学特征。采用高效液相色谱法分析血苯丙氨酸水平。
50.9%的患者为轻度 HPA-无需治疗（NT），25.9%的患者为经典苯丙酮尿症（PKU）表型。共发现 47 种变异类型。主要变异类型为 p.Ala403Val（9.9%）、p.Ala300Ser（9.4%）和 c.1066-11G>A（剪接）（9.4%）。错义突变占突变的 68%，降低了临床影响；14.8%的严重表型病例存在剪接变异。p.Thr380Met 等位基因仅存在于轻度 HPA-NT 组。c.1066-11G>A（剪接）等位基因与经典 PKU 相关，而 p.Arg408Trp 等位基因与严重症状相关。发现 3 种临床意义不明的变异：c.706+4A>T（剪接）、c.843-5T>C（剪接）和 p.Thr323=。其中，c.843-5T>C（剪接）等位基因纯合的患者表现为经典 PKU 表型。70%接受四氢生物蝶呤（BH4）检测的患者有反应。对 BH4 治疗有反应的表型多为轻度表型。
基因型是决定 PKU 表型的主要因素。确定鉴定的基因突变与表型特征之间的关系，将为每位患者提供特定管理方式的非常重要的数据。
