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Fluoropyrimidines (FLs) have been widely used for more than 60 years against a range of solid tumors and still remains the cornerstone for the treatment of colorectal, gastric, and breast cancer. Here, we performed an economic analysis to estimate the cost of DPYD-guided toxicity management and the clinical benefit expressed as quality adjusted life years (QALYs) in a large group of 571 individuals of Italian origin suffering from cancer and treated with a fluoropyrimidines-based chemotherapy. Individuals suffering from cancer with a histologically confirmed diagnosis of cancer, who received a fluoropyrimidines-based treatment, were retrospectively genotyped in the DPYD gene. Effectiveness was measured as survival of individuals from chemotherapy, while study data on safety and efficacy as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. DPYD extensive metabolizers (528 individuals) had greater effectiveness and lesser cost, representing a cost-saving option over DPYD intermediate and poor metabolizers (43 individuals) with mean QALYs of 4.18 (95%CI: 3.16-5.55) versus 3.02 (95%CI: 1.94-4.25), respectively. Our economic analysis showed that there are some indications for differences in survival between the two groups (p > 0.05), while the cost of DPYD extensive metabolizers was significantly lower (p < 0.01) compared with those belonging to the group of intermediate/poor metabolizers. These findings suggest that DPYD-guided fluoropyrimidines treatment represent a cost-saving choice for individuals suffering from cancer in the Italian healthcare setting., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)