ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)

Haploinsufficiency phenotype comments:

Homozygous or compound heterozygous mutation in the DPYD cause Dihydropyrimidine dehydrogenase deficiency (OMIM: 274270). Asymptomatic individuals with biallelic variants have also been reported, suggesting reduced penetrance (PMID: 9254861, 12668826). Carter 2010 has reported a maternally inherited heterozygous exon 6 deletion in a patient with autism spectrum disorder, however the mother is healthy with no history of academic or social difficulties. (PMID:21114665). Xu 2013 reported de novo missense and nonsense variants in 2 individuals in a schizophrenia cohort. DPYD deficiency was also confirmed in the missense variant carrier. However, neither of these individuals have intellectual disability or autistic features (PMID:23042115). Other de novo deletions involving DPYD gene in the literature are all larger than 1 Mb (PMID:21114665, 24038936), therefore not informative for this evaluation. Taken together, there is not enough evidence from the literature to support dosage sensitivity of DPYD gene at this time. In addition, homozygous and heterozygous mutation carriers are at increased risk of developing adverse reactions after the administration of the antineoplastic drug 5-fluorouracil (5FU), which is also catabolized by the DPYD enzyme (PMID:23988873, Clinical Pharmacogenetics Implementation Consortium Guidelines). Homozygotes may have higher risk while risk in heterozygotes may be lower. The Guideline provides dosing recommendations based on DPYD genotype.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity