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Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ∼ 2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score.Ten de novo mutations in three previously identified disease genes (TUBA!A (n = 2), SCN8A (n = 1) and KDM5C (n = 1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome χ in two known disease genes, LI CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes. [ABSTRACT FROM AUTHOR]

The advent of whole-exome next-generation sequencing ( WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½-year old female patient with a 2-year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work-up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di-deoxy sequencing. WES revealed a de novo non-synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future. [ABSTRACT FROM AUTHOR]

With the wide acceptance of the long-chain (LC) n-3 PUFA EPA and DHA as important nutrients playing a role in the amelioration of certain diseases, efforts to understand factors affecting intakes of these fatty acids along with potential strategies to increase them are vital. Widespread aversion to oil-rich fish, the richest natural source of EPA and DHA, highlights both the highly suboptimal current intakes in males and females across all age-groups and the critical need for an alternative supply of EPA and DHA. Poultry meat is a popular and versatile food eaten in large quantities relative to other meats and is open to increased LC n-3 PUFA content through manipulation of the chicken's diet to modify fatty acid deposition and therefore lipid composition of the edible tissues. It is therefore seen as a favourable prototype food for increasing human dietary supply of LC n-3 PUFA. Enrichment of chicken breast and leg tissue is well established using fish oil or fishmeal, but concerns about sustainability have led to recent consideration of algal biomass as an alternative source of LC n-3 PUFA. Further advances have also been made in the quality of the resulting meat, including achieving acceptable flavour and storage properties as well as understanding the impact of cooking on the retention of fatty acids. Based on these considerations it may be concluded that EPA- and DHA-enriched poultry meat has a very positive potential future in the food chain. [ABSTRACT FROM AUTHOR]

Background: Infection with the flavivirus West Nile virus (WNV) is a growing problem across the United States, where there is a case-fatality rate of 15%-29% in individuals >70 years old and no consistently effective treatment. Susceptibility to WNV disease in inbred strains of mice was mapped to a nonsense mutation in the gene encoding the 1b isoform of 2'-5'-oligoadenylate synthetase (OAS), a member of the OAS/RNase L system of innate viral resistance. Genetic susceptibility to severe WNV disease in humans has not been determined.Methods: We sequenced each exon within all OAS and RNASEL genes in 33 individuals hospitalized with WNV infection in Houston to assess if there is a defect in this system in patients with severe WNV disease.Results: Sequencing did not reveal any insertions, deletions, or nonsense mutations in any OAS or RNASEL gene. However, comparison of the exonic sequences between case patients and control subjects identified 23 single nucleotide polymorphisms (SNPs), including a synonymous SNP in OASL exon 2 (rs3213545), in which the reference allele occurred at a higher frequency in case patients (P < .004).Conclusion: Because the reference allele contains a splice enhancer site, our finding suggests that the RNA transcripts generated from this allele may undergo increased splicing, which results in a dominant-negative OASL isozyme similar to the nonsense/truncation mutant form of Oas1b in mice. [ABSTRACT FROM AUTHOR]