A novel stop-gain mutation in DPYS gene causing Dihidropyrimidinase deficiency, a case report

Abstract

Background: Dihidropyrimidinase (DHP) deficiency is an inherited inborn error of pyrimidine metabolism with a variable clinical presentation and even asymptomatic subjects. Dihydropyrimidinase is encoded by the DPYS gene, thus pathogenic mutations in this gene can cause DHP deficiency. To date, several variations in the DPYS gene have been reported but only 23 of them have been confirmed to be pathogenic. Therefore, the biochemical, clinical and genetic aspects of this disease are still unclear. Case presentation: Here, we report a 22-year-old woman with DHP deficiency. To identify the genetic cause of DHP deficiency in this patient, Whole Exome Sequencing (WES) was performed, which revealed a novel homozygote stop gain mutation (NM_001385: Exon 9, c.1501 A > T, p.K501X) in the DPYS gene. Sanger sequencing was carried out on proband and other family members in order to confirm the identified mutation. According to the homozygote genotype of the patient and heterozygote genotype of her parents, the autosomal recessive pattern of inheritance was confirmed. In addition, bioinformatics analysis of the identified variant using Mutation Taster and T-Coffee Multiple Sequence Alignment showed the pathogenicity of mutation. Moreover, mRNA expression level of DPYS gene in the proband's liver biopsy showed about 6-fold reduction compared to control, which strongly suggested the pathogenicity of the identified mutation. Conclusions: This study identified a novel pathogenic stop gain mutation in DPYS gene in a DHP deficient patient. Our findings can improve the knowledge about the genetic basis of the disease and also provide information for accurate genetic counseling for the families at risk of these types of disorders.

The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature

“…Although the gastrointestinal system is the second most common organ involvement in DHP early in childhood, our patient developed gastrointestinal symptoms at 18 yr, underlining the potential for delayed onset and emphasizing the importance of regular screening for complications that may emerge or intensify at any age. A similar late-onset manifestation, liver dysfunction leading to cirrhosis at 22 yr, was reported in a previous case (Mirzaei et al 2020). These findings highlight the need for ongoing screening and examination for anticipated complications.…”

“…To date, most of the identified variants are missense variants, with at least 19 pathogenic variants reported. Other pathogenic alterations have also been identified, including three nonsense variants, three deletions, one insertion, and two splice site variants (Hamajima et al 1998;van Kuilenburg et al 2007van Kuilenburg et al , 2010Yeung et al 2013;Nakajima et al 2016;Hishinuma et al 2017;Tsuchiya et al 2019;Mirzaei et al 2020). Twenty-six percent of the variants were distributed in exon 1, and 59% were spread between exons 5 and 8.…”

“…Articles published between 1990 and the present were reviewed, focusing on phenotypic variability. The review included 34 patients from 14 published reports, incorporating our patient and culminating in a total of 35 patients (Table 3; Duran et al 1990;Henderson et al 1993;Assmann et al 1997;Putman et al 1997;van Gennip et al 1997;van Kuilenburg et al 2007van Kuilenburg et al , 2010Yeung et al 2013;Akai et al 2015;Nakajima et al 2016Nakajima et al , 2017Tsuchiya et al 2019;Mirzaei et al 2020). Among the 35 patients, nine patients were asymptomatic at the time of diagnosis (Ohba et al 1994;Hamajima et al 1998;Sumi et al 1998;Kuhara et al 2003;Hishinuma et al 2017), with two adult siblings (36 and 37 yr old, respectively) (Sumi et al 1998).…”