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Genome sequencing reveals a novel genetic mechanism underlying dihydropyrimidine dehydrogenase deficiency: A novel missense variant c.1700G>A and a large intragenic inversion in DPYD spanning intron 8 to intron 12
Author(s) -
Kuilenburg André B.P.,
TarailoGraovac Maja,
Meijer Judith,
Drogemoller Britt,
Vockley Jerry,
Maurer Dirk,
Dobritzsch Doreen,
Ross Colin J.,
Wasserman Wyeth,
Meinsma Rutger,
Zoetekouw Lida,
Karnebeek Clara D.M.
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23538
Subject(s) - dpyd , biology , genetics , sanger sequencing , missense mutation , exome , loss of heterozygosity , exome sequencing , compound heterozygosity , phenotype , gene , dna sequencing , allele , genotype , pharmacogenetics
Abstract Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with a variable clinical presentation. A family with three DPD‐deficient patients presented with unusual clinical phenotypes including pregnancy‐induced symptoms, transient visual impairment, severe developmental delay, cortical blindness, and delayed myelination in the brain. DPYD Sanger sequencing showed heterozygosity for the c.1905+1G>A mutation and a novel missense variant c.1700G>A (p.G567E). The recombinantly expressed p.G567E DPD variant showed increased temperature lability probably caused by structural rearrangements within the DPD protein. Genome sequencing of the affected son established compound heterozygosity for the c.1700G>A and an imperfect 115,731 bp inversion with breakpoints at chr1: 98,113,121 (intron 8) and chr1: 97,997,390 (intron 12) of the DPYD associated with a 4 bp deletion (chr1: 97,997,386_97,997,389del). Whole exome and mitochondrial DNA analyses for the mother and daughter did not reveal additional mutated genes of significance. Thus, an inversion in DPYD should be considered in patients with an inconclusive genotype or unusual clinical phenotype.