Biochemical and molecular features of tetrahydrobiopterin deficiency in Fujian Province, southeastern China

Xiaolong Qiu; Peiran Zhao; Jinying Luo; Guilin Li; Lin Deng; Yinglin Zeng; Liangpu Xu; Jinfu Zhou

doi:10.3389/fgene.2023.1250568

Biochemical and molecular features of tetrahydrobiopterin deficiency in Fujian Province, southeastern China

Front Genet. 2023 Aug 11:14:1250568. doi: 10.3389/fgene.2023.1250568. eCollection 2023.

Authors

Xiaolong Qiu¹, Peiran Zhao¹, Jinying Luo², Guilin Li³, Lin Deng², Yinglin Zeng¹, Liangpu Xu¹, Jinfu Zhou¹

Affiliations

¹ Genetic Diagnosis and Therapy Center, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Maternity and Child Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China.
² Obstetrics and Gynecology Department, Fujian Maternity and Child Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China.
³ Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China.

Abstract

The estimated prevalence of tetrahydrobiopterin deficiency (BH4D) and the mutational spectrum of the causal 6-pyruvoyl-tetrahydropterin synthase (PTS) gene vary widely according to race and region. This study assessed the prevalence and genetic characteristics of BH4D in Fujian Province, southeastern China. A total of 3,204,067 newborns were screened between 2012 and 2022 based on the phenylalanine level and the phenylalanine/tyrosine ratio in dried blood spots. Differential diagnosis was determined by the urine purine spectrum, dihydropteridine reductase activity in red blood cells, and genetic testing. The PTS mutation spectrum and genotypes were determined by next-generation sequencing. A total of 189 newborns were diagnosed with hyperphenylalaninemia (HPA) over the study period, including 159 with phenylalanine hydroxylase deficiency and 30 with BH4D. Therefore, the prevalence of BH4D in Fujian was 9.36 per 1,000,000 live births (30/3,204,067) and the proportion of BH4D among patients with HPA was 15.87% (30/189). A total of 58 PTS alleles were identified in the 29 patients with PTS deficiency (PTPSD), and those alleles were composed of 10 different variants, including eight missense variants and two splice-site variants. The most prevalent variants were c.155A>G, p.Asn52Ser (44.83%); c.259C>T, p.Pro87Ser (39.66%); and c.84-291A>G, p.Tyr27Argfs*8 (3.45%). The predominant genotype was c [155A>G]; [259C>T] (11/29, 37.93%). The prevalence of BH4D and the spectrum of associated PTS mutations were successfully determined for the first time in Fujian Province, southeastern China. Since the mutation spectrum of PTS is region-specific, such data will facilitate molecular diagnosis and genetic counseling in PTPSD cases.

Keywords: 6-pyruvoyl-tetrahydropterin synthase; newborn screening; southeastern China; tetrahydrobiopterin deficiency; variant spectrum.

Grants and funding

This work was supported by the Key Project on Science and Technology Program of the Fujian Health Commission (Grant No. 2021ZD01002), Natural Science Foundation of Fujian Province (Grant No. 2020J01327), Fujian Provincial Health Technology Project (Grant Nos 2020GGB017 and 2022CXA033), and Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant No. 2020Y9143).