Journal Article

Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3)

van Kuilenburg, André B. P, Mul, Adri N. P. M, Fowler, Brian, Rubio-Gozalbo, M. Estela, Sass, Jörn Oliver, Hennermann, Julia B, Nicolai, Joost, Hoovers, Jan M. N, Macke, Klaus, Meinsma, Rutger, Miny, Peter, Ylstra, Bauke, Bierau, Jörgen, Meijer, Judith, Weber, Peter, Mori, Andrea Capone, Zoetekouw, Lida, de Die-Smulders, Christine E. M, Hennekam, Raoul C. M, Vijzelaar, Raymon

2009

Overview

Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.

• Publisher: Berlin/Heidelberg : Springer-Verlag,Springer-Verlag,Springer,Springer Nature B.V
• Subject: Analysis / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Child, Preschool / Chromosomes / Chromosomes, Human, Pair 1 - genetics / Classical genetics, quantitative genetics, hybrids / Comparative Genomic Hybridization / Dehydrogenases / Dihydropyrimidine Dehydrogenase Deficiency - genetics / Dihydrouracil Dehydrogenase (NADP) - genetics / DNA Mutational Analysis / Enzymes / Exons / Female / Fundamental and applied biological sciences. Psychology / Gene Function / Gene Rearrangement / Genes / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Human / Human Genetics / Humans / In Situ Hybridization, Fluorescence / Infant / Male / Medical research / Medicine, Experimental / Metabolic Diseases / Metabolic disorders / Molecular Medicine / Molecular Sequence Data / Mutation / Original Investigation / Patients / Pediatrics / Pyrimidines / Pyrimidines - analysis / Sequence Deletion / Toxicity