Classic galactosemia (CG) is a potentially lethal inborn error of metabolism, if untreated, that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the middle enzyme of the Leloir pathway of galactose metabolism. While newborn screening and rapid dietary restriction of galactose prevent or resolve the potentially lethal acute symptoms of CG, by midchildhood, most treated patients experience significant complications. The mechanisms underlying these long-term deficits remain unclear. Here we introduce a new GALT-null rat model of CG and demonstrate that these rats display cataracts, cognitive, motor, and growth phenotypes reminiscent of patients outcomes.We further apply the GALT-null rats to test how well blood biomarkers, typically followed in patients, reflect metabolic perturbations in other, more relevant tissues. Our results document that the relative levels of galactose metabolites seen in GALT deficiency differ widely by tissue and age, and that red blood cell Gal-1P, the marker most commonly followed in patients, shows no significant association with Gal-1P in other tissues. The work reported here establishes our outbred GALT-null rats as an effective model for at least four complications characteristic of CG, and sets the stage for future studies addressing mechanism and testing the efficacy of novel candidate interventions. K E Y W O R D Scognitive, galactosemia, GALT, metabolite, model, rat

Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

Motivation There is widespread interest in identifying genetic variants that exhibit parent-of-origin effects (POEs) wherein the effect of an allele on phenotype expression depends on its parental origin. POEs can arise from different phenomena including genomic imprinting and have been documented for many complex traits. Traditional tests for POEs require family data to determine parental origins of transmitted alleles. As most genome-wide association studies (GWAS) sample unrelated individuals (where allelic parental origin is unknown), the study of POEs in such datasets requires sophisticated statistical methods that exploit genetic patterns we anticipate observing when POEs exist. We propose a method to improve discovery of POE variants in large-scale GWAS samples that leverages potential pleiotropy among multiple correlated traits often collected in such studies. Our method compares the phenotypic covariance matrix of heterozygotes to homozygotes based on a Robust Omnibus Test. We refer to our method as the Parent of Origin Inference using Robust Omnibus Test (POIROT) of multiple quantitative traits. Results Through simulation studies, we compared POIROT to a competing univariate variance-based method which considers separate analysis of each phenotype. We observed POIROT to be well-calibrated with improved power to detect POEs compared to univariate methods. POIROT is robust to non-normality of phenotypes and can adjust for population stratification and other confounders. Finally, we applied POIROT to GWAS data from the UK Biobank using BMI and two cholesterol phenotypes. We identified 338 genome-wide significant loci for follow-up investigation. Availability The code for this method is available at https://github.com/staylorhead/POIROT-POE. Supplementary information Supplementary data are available at Bioinformatics online.

MotivationThere is widespread interest in identifying genetic variants that exhibit parent-of-origin effects (POEs) wherein the effect of an allele on phenotype expression depends on its parental origin. POEs can arise from different phenomena including genomic imprinting and have been documented for many complex traits. Traditional tests for POEs require family data to determine parental origins of transmitted alleles. As most genome-wide association studies (GWAS) instead sample unrelated individuals (where allelic parental origin is unknown), the study of POEs in such datasets requires sophisticated statistical methods that exploit genetic patterns we anticipate observing when POEs exist. We propose a method to improve discovery of POE variants in large-scale GWAS samples that leverages potential pleiotropy among multiple correlated traits often collected in such studies. Our method compares the phenotypic covariance matrix of heterozygotes to homozygotes based on a Robust Omnibus Test. We refer to our method as the Parent of Origin Inference using Robust Omnibus Test (POIROT) of multiple quantitative traits.ResultsThrough simulation studies, we compared POIROT to a competing univariate variance-based method which considers separate analysis of each phenotype. We observed POIROT to be well-calibrated with improved power to detect POEs compared to univariate methods. POIROT is robust to non-normality of phenotypes and can easily adjust for population stratification and other confounders. Finally, we applied POIROT to a GWAS of quantitative anthropometric measures at birth. We identified two loci of suggestive significance for follow-up investigation.

Background In patients with complex coronary artery disease (CAD), women favored coronary artery bypass grafting surgery (CABG) compared to percutaneous coronary intervention (PCI) at 5 years in the SYNTAX trial, whereas mortality rates after PCI and CABG were not different in men. On the other hand, poor outcomes of women undergoing PCI were not observed in the PRECOMBAT and BEST trials. The long-term optimal revascularization strategy according to gender has not been fully evaluated. Purpose In the SYNTAX Extended Survival (SYNTAXES) study, no significant difference existed in all-cause death between PCI and CABG at 10 years. This study aimed to assess treatment effect of PCI and CABG for 10-year all-cause death according to gender. Methods The SYNTAXES study evaluated vital status up to 10 years in 1,800 patients with de novo three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to treatment with CABG or PCI in the SYNTAX trial, and the pre-specified primary endpoint was all-cause death at 10 years. In this prespecified analysis, all-cause death at 10 years according to gender in patients undergoing PCI or CABG was evaluated. Results Of 1800 patients, 402 (22.3%) were women and 1398 (77.7%) were men. In women, the rate of mortality was significantly higher in the PCI arm at 5 years than in the CABG arm (19.3% vs. 10.3%; Log-rank p=0.010, Figure A), but the rates of mortality were not different at 10 years between the PCI and CABG arms (33.0% vs. 32.5%; Log-rank p=0.600, Figure A). In men, the mortality rate tended to be higher in the PCI arm at 10 years than in the CABG arm (27.0% vs. 22.5%; Log-rank p=0.082, Figure B), although the mortality rates were not different at 5 years between the PCI and CABG arms (12.4% vs. 12.3%; Log-rank p=0.957, Figure B). Conclusion The efficacy of CABG observed at 5 years disappeared at 10 years in women, whereas the efficacy of CABG became apparent after 5 years in men. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Erasmus University Medical Centre, Rotterdam, Netherlands, reference: MEC-2016-716

Whole-exome sequencing (WES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for WES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed whole-exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, KLF4, SHROOM3, SMC3, TP63, and TBX3 in seven families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

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