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).
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.
van Kuilenburg
André B P
AB
Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.b.vankuilenburg@amc.uva.nl
Meijer
Judith
J
Mul
Adri N P M
AN
Hennekam
Raoul C M
RC
Hoovers
Jan M N
JM
de Die-Smulders
Christine E M
CE
Weber
Peter
P
Mori
Andrea Capone
AC
Bierau
Jörgen
J
Fowler
Brian
B
Macke
Klaus
K
Sass
Jörn Oliver
JO
Meinsma
Rutger
R
Hennermann
Julia B
JB
Miny
Peter
P
Zoetekouw
Lida
L
Vijzelaar
Raymon
R
Nicolai
Joost
J
Ylstra
Bauke
B
Rubio-Gozalbo
M Estela
ME
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
D011743:Pyrimidines; D042943:Dihydrouracil Dehydrogenase (NADP)