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)

作者：van Kuilenburg Andre B P^*; Meijer Judith; Mul Adri N P M; Hennekam Raoul C M; Hoovers Jan M N; de Die Smulders Christine E M; Weber Peter; Mori Andrea Capone; Bierau Jorgen; Fowler Brian; Macke Klaus; Sass Joern Oliver; Meinsma Rutger; Hennermann Julia B; Miny Peter; Zoetekouw Lida; Vijzelaar Raymon; Nicolai Joost; Ylstra Bauke; Rubio Gozalbo M Estela

来源：Human Genetics, 2009, 125(5-6): 581-590.

DOI：10.1007/s00439-009-0653-6

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.

• 出版日期2009-6