title: 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).
abstract: 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.
authors.affiliation: Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.b.vankuilenburg@amc.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Judith
authors.initials: J
authors.lastname: Meijer
authors.forename: Adri N P M
authors.initials: AN
authors.lastname: Mul
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Jan M N
authors.initials: JM
authors.lastname: Hoovers
authors.forename: Christine E M
authors.initials: CE
authors.lastname: de Die-Smulders
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Andrea Capone
authors.initials: AC
authors.lastname: Mori
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.forename: Klaus
authors.initials: K
authors.lastname: Macke
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.forename: Rutger
authors.initials: R
authors.lastname: Meinsma
authors.forename: Julia B
authors.initials: JB
authors.lastname: Hennermann
authors.forename: Peter
authors.initials: P
authors.lastname: Miny
authors.forename: Lida
authors.initials: L
authors.lastname: Zoetekouw
authors.forename: Raymon
authors.initials: R
authors.lastname: Vijzelaar
authors.forename: Joost
authors.initials: J
authors.lastname: Nicolai
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: M Estela
authors.initials: ME
authors.lastname: Rubio-Gozalbo
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005091:Exons; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D011743:Pyrimidines / Q000032:analysis; D017384:Sequence Deletion
chemical_list: D011743:Pyrimidines; D042943:Dihydrouracil Dehydrogenase (NADP)