Search

The DPYD gene encodes dihydropyrimidine dehydrogenase, the rate‐limiting enzyme for the metabolism of fluoropyrimidines 5‐fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129‐5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single‐nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function‐altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129‐5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129‐5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false‐positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129‐5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity. [ABSTRACT FROM AUTHOR]

The ontogeny of hepatic uridine diphosphate‐glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0–18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC‐MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3‐fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6–10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny–genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine. [ABSTRACT FROM AUTHOR]

We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Obesity is a highly heritable trait and a growing public health problem. African Americans (AAs) are a genetically diverse, yet understudied population with a high prevalence of obesity (BMI >30 kg/m2). Recent studies based upon single-nucleotide polymorphisms (SNPs) have identified genetic markers associated with obesity. However, a large proportion of the heritability of obesity remains unexplained. Copy number variation (CNV) has been cited as a possible source of missing heritability in common diseases such as obesity. We conducted a CNV genome-wide association study of BMI in two African-American cohorts from Genetic Epidemiology Network of Arteriopathy (GENOA) and Hypertension Genetic Epidemiology Network (HyperGEN). We performed independent and identical association analyses in each study, then combined the results in a meta-analysis. We identified three CNVs associated with BMI, obesity, and other obesity-related traits after adjusting for multiple testing. These CNVs overlap the PARK2, GYPA, and SGCZ genes. Our results suggest that CNV may play a role in the etiology of obesity in AAs. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms by which DNA and DNA variation influence diseases, naturally occurring phenotypic variation, and complex biological systems, has been one of the major tasks associated with contemporary human genetics research. The identification and characterization of specific genetic variations that influence particular human diseases and phenotypes is complicated by the fact that most diseases and phenotypes are influenced by many genetic and environmental factors. Thus, the identification of any particular phenotypically relevant factor might be hampered as other relevant factors may obscure its individual effect. Over the years numerous methods and study designs have been described to identify disease causing genes and mutations. One in particular - meiotic or recombination mapping - has received considerable attention over the last 50 years, and has been used widely with varying degrees of success. This review describes the motivation behind, and problems associated with, recombination mapping, in terms of both linkage mapping and linkage disequilibrium mapping. [ABSTRACT FROM AUTHOR]