Maternale uniparentale disomie 14. In de differentiaaldiagnose bij Prader-Willi-syndroom

Maternal uniparental disomy 14 is a rare genetic disorder in which both chromosomes 14 are maternally inherited. The disorder is characterised by neonatal hypotonia and feeding difficulties, intrauterine or later growth retardation, truncal obesity and precocious puberty. During the neonatal period its clinical phenotype shows great similarities with that of Prader-Willi syndrome. We describe two patients with dysmaturity, neonatal hypotonia and feeding difficulties who initially showed clinical signs of Prader-Willi syndrome. However, molecular testing for this disorder was normal. Some years later, additional molecular testing confirmed the diagnosis of maternal uniparental disomy 14. Maternal uniparental disomy 14 shows many phenotypic similarities with Prader-Willi syndrome. In a hypotonic neonate, molecular testing for maternal uniparental disomy 14 should therefore be considered if Prader-Willi syndrome has been exclude

Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843T > C, c.321 + I G > A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.1948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c321 + 1G > A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD premRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines. (C) 2016 Elsevier B.V. All rights reserve

Genetic Analyses in Small for Gestational Age Newborns

Small for gestational age (SGA) can be a result of fetal growth restriction, associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. The aim of the present study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more CNVs and disturbed methylation and sequence variants may be present in genes known to be associated with fetal growth. A prospective cohort study of subjects with a low birthweight for gestational age. The study was conducted at an academic pediatric research institute. A total of 21 SGA newborns with a mean birthweight below the 1st centile and a control cohort of 24 appropriate for gestational age newborns were studied. Array comparative genomic hybridization, genome-wide methylation studies and exome sequencing were performed. The numbers of copy number variations, methylation disturbances and sequence variants. The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern and one sequence variant explaining the SGA. Additional methylation disturbances and sequence variants were present 20 patients. In 19 patients, multiple abnormalities were found. Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We conclude that copy number variations, methylation disturbances and sequence variants all contribute to prenatal growth failure. Such genetic workup can be an effective diagnostic approach in SGA newborn