Background: Deleterious mutations in the human gene phenylalanine hydroxylase (PAH) encoding the phenylalanine hydroxylase enzyme give rise to classic phenylketonuria and hyperphenylalaninemia. Our study was designed to characterize the spectrum of variants in the PAH gene in Saudi patients. Materials and Methods: We screened a cohort of 72 Saudi patients with clinical and biochemical diagnoses of hyperphenylalaninemia at the largest tertiary care center in Saudi Arabia; the King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh. All patient's charts were reviewed under an approved study by Institutional Review Board. Results: Twenty-one different PAH variants were identified among the 144 PAH alleles assessed by targeted gene sequencing. Within the studied cohort, 60 of 72 patients had homozygous mutations with the the remaining 12 being compound heterozygotes. The most prevalent of the disease alleles identified in this study was the p.(Arg252Trp) mutation, which accounted for 38 of 144 alleles (26.4%). With the high incidence of genetic disorders in the population, religiously permissible preventive reproductive measures are a priority in our practice. Prenatal diagnoses carried out on four fetuses revealed two that were homozygous for PAH pathogenic variants. In addition, pre-implantation genetic diagnoses were initiated for 19 families. Eight of these families completed more than one full cycle of treatment, from which one healthy newborn was delivered. Conclusions: This study describes the spectrum of PAH variants in the Saudi population and highlights the molecular heterogeneity underlying phenylketonuria and hyperphenylalaninemia. These results add to the existing knowledge about PAH variants in Middle Eastern Countries. These results can be further translated to provide: informed counseling; cascade carrier testing in extended family members; and pre-marital screening.

中文翻译：

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鉴定沙特阿拉伯苯丙氨酸羟化酶缺乏症的变异体。

背景：编码苯丙氨酸羟化酶的人类苯丙氨酸羟化酶 (PAH) 基因发生有害突变会导致典型的苯丙酮尿​​症和高苯丙氨酸血症。我们的研究旨在表征沙特患者 PAH 基因的变异谱。材料和方法：我们在沙特阿拉伯最大的三级医疗中心筛选了 72 名临床和生化诊断为高苯丙氨酸血症的沙特患者；费萨尔国王专科医院和研究中心 (KFSH&RC)，利雅得。所有患者的图表均根据机构审查委员会批准的研究进行了审查。结果：在通过靶向基因测序评估的 144 个 PAH 等位基因中鉴定出 21 个不同的 PAH 变体。在研究队列中，72 名患者中有 60 名具有纯合突变，其余 12 名是复合杂合子。在这项研究中发现的最普遍的疾病等位基因是 p.(Arg252Trp) 突变，占 144 个等位基因中的 38 个 (26.4%)。由于人口中遗传疾病的发病率很高，宗教上允许的预防性生殖措施是我们实践中的优先事项。对四个胎儿进行的产前诊断显示两个胎儿是 PAH 致病变异的纯合子。此外，还对19个家庭进行了植入前基因诊断。其中八个家庭完成了一个以上的完整治疗周期，并从中分娩了一名健康的新生儿。结论：本研究描述了沙特人口中 PAH 变异的范围，并强调了苯丙酮尿症和高苯丙氨酸血症背后的分子异质性。这些结果增加了关于中东国家 PAH 变体的现有知识。这些结果可以进一步转化为提供： 知情咨询；在大家庭成员中进行级联载体测试；和婚前筛查。