Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China

Abstract

Background: Tetrahydrobiopterin (BH₄ ) deficiency is an autosomal recessive disorder, which is caused by an enzyme deficiency involved in its synthetic or metabolic pathways. Clinical symptoms may include microcephaly, hypoevolutism, severe ataxia, and seizures. The purposes of this study are to analyze the genotype-phenotype and the pedigree of the first case of BH₄ deficiency in the Uygur of China.

Methods: (a) This patient received tandem mass spectrometry, urinary neopterin and biopterin analysis, and determination of dihydropteridine reductase (DHPR) activity in dried blood spots. (b) Blood DNA samples of this patient and her three family members were collected for gene sequencing and mutation analysis.

Results: (a) The basic urinary neopterin and biopterin were 1.07 mmol/mol Cr and 3.12 mmol/mol Cr, respectively, and biopterin percentage was 74.42%. The DHPR activity of this patient was 31.11% of normal control. (b) Sanger sequencing of PAH gene in this patient was negative but positive of her sister, which carries 2 heterozygous mutation c.781C>T and c.1238G>C. Next-generation sequencing on the patient identified a homozygous mutation in the quinoid dihydropteridine reductase (QDPR) gene at c.508G>A, which was confirmed by Sanger sequencing.

Conclusion: (a) The patient was the first case of clinical diagnosis of BH₄ deficiency in the Uighur. And there are two types of hyperphenylalaninemia (HPA) in the same family. (b) The mild HPA patient with severe nervous system damage should pay more attention to the BH₄ deficiency. (c) Using next-generation sequencing technology can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.

Keywords: Uygur; dihydropteridine reductase; gene mutation; hyperphenylalaninemia; tetrahydrobiopterin deficiency.

Figure 1

The sister and parents’ PAH gene Sanger sequencing results.(As can be seen from the figure, the mutation gene of the sister was derived from the parental PAH mutant genes c.781C>T (p.R261RX) and c.1238G>C (p.R413RP), respectively)

Figure 2

Next‐generation sequencing and QDPR Sanger sequencing results in the patient with DHPR deficiency.(A: Next‐generation sequencing showed homozygous missense mutation c.508G>A in QDPR of the patient. B: Sanger sequencing traces confirmed the change c.508G>A, QDPR)

Figure 3

Segregation analysis of QDPR gene mutations and pedigree of the family examined in the present