Dihydropyrimidine dehydrogenase deficiency: Homozygosity for an extremely rare variant in DPYD due to uniparental isodisomy of chromosome 1

André B. P. van Kuilenburg, Judith Meijer, Rutger Meinsma, Belén Pérez-Dueñas, Marielle Alders, Zahurul A. Bhuiyan, Rafael Artuch, Raoul C. M. Hennekam

Research output: Chapter in Book/Report/Conference proceedingChapterAcademicpeer-review

Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.
Original languageEnglish
Title of host publicationJIMD Reports
PublisherSpringer
Pages65-69
Volume45
DOIs
Publication statusPublished - 2019

Publication series

NameJIMD Reports
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312

Cite this

van Kuilenburg, A. B. P., Meijer, J., Meinsma, R., Pérez-Dueñas, B., Alders, M., Bhuiyan, Z. A., ... Hennekam, R. C. M. (2019). Dihydropyrimidine dehydrogenase deficiency: Homozygosity for an extremely rare variant in DPYD due to uniparental isodisomy of chromosome 1. In JIMD Reports (Vol. 45, pp. 65-69). (JIMD Reports). Springer. https://doi.org/10.1007/8904_2018_138
van Kuilenburg, André B. P. ; Meijer, Judith ; Meinsma, Rutger ; Pérez-Dueñas, Belén ; Alders, Marielle ; Bhuiyan, Zahurul A. ; Artuch, Rafael ; Hennekam, Raoul C. M. / Dihydropyrimidine dehydrogenase deficiency: Homozygosity for an extremely rare variant in DPYD due to uniparental isodisomy of chromosome 1. JIMD Reports. Vol. 45 Springer, 2019. pp. 65-69 (JIMD Reports).
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abstract = "Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.",
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van Kuilenburg, ABP, Meijer, J, Meinsma, R, Pérez-Dueñas, B, Alders, M, Bhuiyan, ZA, Artuch, R & Hennekam, RCM 2019, Dihydropyrimidine dehydrogenase deficiency: Homozygosity for an extremely rare variant in DPYD due to uniparental isodisomy of chromosome 1. in JIMD Reports. vol. 45, JIMD Reports, Springer, pp. 65-69. https://doi.org/10.1007/8904_2018_138

Dihydropyrimidine dehydrogenase deficiency: Homozygosity for an extremely rare variant in DPYD due to uniparental isodisomy of chromosome 1. / van Kuilenburg, André B. P.; Meijer, Judith; Meinsma, Rutger; Pérez-Dueñas, Belén; Alders, Marielle; Bhuiyan, Zahurul A.; Artuch, Rafael; Hennekam, Raoul C. M.

JIMD Reports. Vol. 45 Springer, 2019. p. 65-69 (JIMD Reports).

Research output: Chapter in Book/Report/Conference proceedingChapterAcademicpeer-review

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N2 - Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.

AB - Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.

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van Kuilenburg ABP, Meijer J, Meinsma R, Pérez-Dueñas B, Alders M, Bhuiyan ZA et al. Dihydropyrimidine dehydrogenase deficiency: Homozygosity for an extremely rare variant in DPYD due to uniparental isodisomy of chromosome 1. In JIMD Reports. Vol. 45. Springer. 2019. p. 65-69. (JIMD Reports). https://doi.org/10.1007/8904_2018_138