Bernard Keavney

The University of Manchester, Manchester, England, United Kingdom

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Publications (93)774.82 Total impact

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    ABSTRACT: Although it is widely believed that IL-27 is anti-inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with Th17 cytokines are unclear. Our aims were to establish the relationships between IL-27 and pro-inflammatory cytokines, including IL-17A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL-27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL-27 including a subunit encoded by Epstein-Barr virus-induced gene 3 (EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL-27 has been reported to inhibit IL-17A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL-27 with other pro-inflammatory cytokines. We verified that IL-27 inhibited IL-17A production by human peripheral blood T cells in vitro, but not that it stimulated IL-10 secretion. Importantly, addition of IL-17A decreased IL-27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL-27 and IL-17A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation.
    Clinical & Experimental Immunology 06/2014; · 3.41 Impact Factor
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    ABSTRACT: To quantify any risk of atrial fibrillation (AF) associated with ivabradine treatment by meta-analysis of clinical trial data.
    Heart (British Cardiac Society) 06/2014; · 5.01 Impact Factor
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    ABSTRACT: Although primary percutaneous coronary intervention (PPCI) has revolutionised treatment of myocardial infarction, ischaemia-reperfusion (I/R) injury remains an important complication. Microvascular obstruction (MVO) is one component of I/R injury, and is of prognostic significance independent of infarct size. We have previously demonstrated changes in T-lymphocyte counts in the blood following PPCI for STEMI. The goal of this study was to investigate a potential role for T-cells in myocardial I/R injury.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A20. · 5.01 Impact Factor
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    ABSTRACT: : Genome-wide association studies (GWAS) have identified genetic variants in nine chromosomal regions that are associated with atrial fibrillation (AF). The mechanisms underlying these associations are unknown. To investigate these mechanisms, we mapped associations between single nucleotide polymorphisms (SNPs) and allelic expression of candidate genes in the region of interest.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A123-A124. · 5.01 Impact Factor
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    ABSTRACT: Objective Congenital cardiac defects represent the most common group of birth defects, affecting an estimated six per 1000 births. Genetic characterization of patients and families with cardiac defects has identified a number of genes required for heart development. Yet, despite the rapid pace of these advances, mutations affecting known genes still account for only a small fraction of congenital heart defects suggesting that many more genes and developmental mechanisms remain to be identified.DesignIn this study, we reviewed 1694 described cases of patients with cardiac defects who were determined to have a significant chromosomal imbalance (a deletion or duplication). The cases were collected from publicly available databases (DECIPHER, ISCA, and CHDWiki) and from recent publications. An additional 68 nonredundant cases were included from the University of Michigan. Cases with multiple chromosomal or whole chromosome defects (trisomy 13, 18, 21) were excluded, and cases with overlapping deletions and/or insertions were grouped to identify regions potentially involved in heart development.ResultsSeventy-nine chromosomal regions were identified in which 5 or more patients had overlapping imbalances. Regions of overlap were used to determine minimal critical domains most likely to contain genes or regulatory elements involved in heart development. This approach was used to refine the critical regions responsible for cardiac defects associated with chromosomal imbalances involving 1q24.2, 2q31.1, 15q26.3, and 22q11.2.Conclusions The pattern of chromosomal imbalances in patients with congenital cardiac defects suggests that many loci may be involved in normal heart development, some with very strong and direct effects and others with less direct effects. Chromosomal duplication/deletion mapping will provide an important roadmap for genome-wide sequencing and genetic mapping strategies to identify novel genes critical for heart development.
    Congenital Heart Disease 05/2014; · 1.01 Impact Factor
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    ABSTRACT: Hypoplastic left heart syndrome (HLHS) is a serious congenital cardiovascular malformation resulting in hypoplasia or atresia of the left ventricle, ascending aorta, and aortic and mitral valves. Diminished flow through the left side of the heart is clearly a key contributor to the condition, but any myocardial susceptibility component is as yet undefined. Using recent advances in the field of induced pluripotent stem cells (iPSCs), we have been able to generate an iPSC model of HLHS malformation and characterize the properties of cardiac myocytes (CMs) differentiated from these and control-iPSC lines. Differentiation of HLHS-iPSCs to cardiac lineages revealed changes in the expression of key cardiac markers and a lower ability to give rise to beating clusters when compared with control-iPSCs and human embryonic stem cells (hESCs). HLHS-iPSC-derived CMs show a lower level of myofibrillar organization, persistence of a fetal gene expression pattern, and changes in commitment to ventricular versus atrial lineages, and they display different calcium transient patterns and electrophysiological responses to caffeine and β-adrenergic antagonists when compared with hESC- and control-iPSC-derived CMs, suggesting that alternative mechanisms to release calcium from intracellular stores such as the inositol trisphosphate receptor may exist in HLHS in addition to the ryanodine receptor thought to function in control-iPSC-derived CMs. Together our findings demonstrate that CMs derived from an HLHS patient demonstrate a number of marker expression and functional differences to hESC/control iPSC-derived CMs, thus providing some evidence that cardiomyocyte-specific factors may influence the risk of HLHS.
    Stem cells translational medicine. 03/2014;
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    ABSTRACT: Statins are one of the most potent drugs in delaying age-related inflammatory changes in the arterial vessel wall, slowing down the progression of atherosclerosis. Statins have also been shown to abrogate telomere-attributed cardiovascular risk. The goal of our study was to explore a potential effect of atorvastatin on telomerase activity in peripheral blood mononuclear cells (PBMCs) and T-lymphocytes (T cells). Methods and Results Treatment with pharmacologically relevant concentrations (0.1-0.3 μM) of atorvastatin resulted in a 6-fold increase of telomerase activity (TA) (p<0.0001) in human and mouse PBMCs and CD4 T cells, translating into moderate proliferation of T lymphocytes. In contrast, high doses of atorvastatin (2 - 5 μM) or the addition of LDL cholesterol completely inhibited proliferation, thereby abrogating telomerase activity. The proliferative effect of atorvastatin was ablated by the absense of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT). Using transgenic GFP-mTert reporter mice, we observed a decrease in telomerase-positive lymphocytes from 30% to 15% during the first 5 months of age (p<0.01). This suggests that the decrease in immune cell turnover during normal development and maturation is mirrored by a reduction in telomerase activity in lymphocytes in-vivo. Conclusion Atorvastatin and cholesterol have opposing effects on telomerase in mononuclear cells and T-lymphocytes. Our study suggests a link between cholesterol metabolism and telomere-related cardiovascular risk.
    Atherosclerosis 01/2014; · 3.71 Impact Factor
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    ABSTRACT: Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.
    The American Journal of Human Genetics 11/2013; · 11.20 Impact Factor
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    ABSTRACT: Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.
    Annals of Human Genetics 08/2013; · 2.22 Impact Factor
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    ABSTRACT: Gastrointestinal (GI) bleeding following percutaneous coronary intervention (PCI) is associated with increased mortality. ACCF/AHA/SCAI guidelines recommend prophylaxis to prevent GI bleeding in patients, with the highest GI bleeding risks taking dual-antiplatelet therapy (DAPT). The REPLACE risk score identifies factors predictive of peri-PCI bleeding from vascular access and non-access sites. We determined whether high bleeding risk acute coronary syndrome (ACS) patients taking DAPT were appropriately provided with GI prophylaxis and investigated the association between age and clinical presentation on the likelihood of receiving prophylactic therapy. This is a retrospective analysis of all non-elective PCI patients at a single center between May and December 2008 stratified by age (<65, 65-74, and ≥75 years). REPLACE scores were calculated and discharge medication was obtained from case records. Complete discharge medication data were available for 800 patients (median age, 63 years; 45.1% with ST-elevation myocardial infarction [STEMI]). A total of 370 patients (46.3%) were high bleeding risk (REPLACE scores ≥10), including all patients ≥75 years (n = 173), 83.5% of patients 65-74 years (n = 177), and 4.8% of patients <65 years (n = 20). In total, 97.6% were discharged on DAPT. Within the high bleeding risk group, 45.1% received GI prophylaxis. Patients 65-74 years were least likely to receive prophylaxis (<65 years, 60%; 65-74 years, 38.4%; ≥75 years, 50.3%; P<.03). Presentation with STEMI was independently associated with a reduced likelihood of GI prophylaxis provision (odds ratio, 0.63; 95% confidence interval, 0.40-0.99; P=.045). Less than half of ACS patients at high bleeding risk taking DAPT are provided with GI prophylaxis. Increased use of objective bleeding risk scores may help guide risk/benefit decisions in patients taking clopidogrel and proton pump inhibitors.
    The Journal of invasive cardiology 08/2013; 25(8):397-401. · 1.57 Impact Factor
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    ABSTRACT: -Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. -We compared genotypes between CHD cases and controls, and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5,814 cases with primary genotype data and 10,056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (OR 0.96 [95% CI 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7,697 cases and 13,125 controls) suggested the presence of association (OR 1.25 [95% CI 1.03-1.51]; p=0.022), but with substantial heterogeneity among contributing studies (I(2)=64.4%), and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR less than 0.05), which together contributed 83% of all cases, yielded no evidence of association (OR 0.97 [95% CI 0.91-1.03]), without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1,781 mothers of CHD cases (829 of whom were genotyped in this study) and 19,861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR 1.13 [95% CI 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. -The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.
    Circulation Cardiovascular Genetics 07/2013; · 6.73 Impact Factor
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    ABSTRACT: Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric β-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 06/2013; · 4.44 Impact Factor
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    ABSTRACT: BACKGROUND: Epidemiological studies indicate a substantial excess familial recurrence of non-syndromic Tetralogy of Fallot (TOF), implicating genetic factors that remain largely unknown. The Rho induced kinase 1 gene (ROCK1) is a key component of the planar cell polarity signalling pathway, which plays an important role in normal cardiac development. The aim of this study was to investigate the role of genetic variation in ROCK1 on the risk of TOF. RESULTS: ROCK1 was sequenced in a discovery cohort of 93 non-syndromic TOF probands to identify rare variants. TagSNPs were selected to capture commoner variation in ROCK1. Novel variants and TagSNPs were genotyped in a discovery cohort of 458 TOF cases and 1331 healthy controls, and positive findings were replicated in a further 209 TOF cases and 1290 healthy controls. Association between genotypes and TOF was assessed using LAMP.A rare SNP (c.807C > T; rs56085230) discovered by sequencing was associated with TOF risk (p = 0.006) in the discovery cohort. The variant was also significantly associated with the risk of TOF in the replication cohort (p = 0.018). In the combined cohorts the odds ratio for TOF was 2.61 (95% CI 1.58-4.30); p < 0.0001. The minor allele frequency of rs56085230 in the cases was 0.02, and in the controls it was 0.007. The variant accounted for 1% of the population attributable risk (PAR) of TOF. We also found significant association with TOF for an uncommon TagSNP in ROCK1, rs288979 (OR 1.64 [95% CI 1.15-2.30]; p = 1.5x10-5). The minor allele frequency of rs288979 in the controls was 0.043, and the variant accounted for 11% of the PAR of TOF. These association signals were independent of each other, providing additional internal validation of our result. CONCLUSIONS: Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.
    BMC Genetics 06/2013; 14(1):57. · 2.81 Impact Factor
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    ABSTRACT: BACKGROUND: Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown. METHODS AND RESULTS: Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p<0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p<0.01). Peak arterial-venous oxygen difference (p<0.05), oxygen uptake (VO2) and power were decreased in patients (both p<0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p<0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p<0.05). CONCLUSION: Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis.
    International journal of cardiology 06/2013; · 6.18 Impact Factor
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    ABSTRACT: We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10(-7)) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10(-5); odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10(-10)). Genotype accounted for ∼9% of the population-attributable risk of ASD.
    Nature Genetics 05/2013; · 35.21 Impact Factor
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    ABSTRACT: OBJECTIVES To determine if 16 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) in Europeans are also associated with T2DM in South Asians and Latinos, and if they can add to the prediction of incident T2DM in a high-risk population.RESEARCH DESIGN AND METHODS In the EpiDREAM prospective cohort study, physical measures, questionnaires, and blood samples were collected from 25,063 individuals at risk for dysglycemia. Sixteen SNPs that have been robustly associated with T2DM in Europeans were genotyped. Among 15,466 European, South Asian, and Latino subjects, we examined the association of these 16 SNPs alone and combined in a gene score with incident cases of T2DM (n = 1,016) that developed during 3.3 years of follow-up.RESULTSNine of the 16 SNPs were significantly associated with T2DM, and their direction of effect was consistent across the three ethnic groups. The gene score was significantly higher among subjects who developed incident T2DM (cases vs. noncases: 16.47 [2.50] vs. 15.99 [2.56]; P = 0.00001). The gene score remained an independent predictor of incident T2DM with an odds ratio of 1.08 (95% CI, 1.05-1.11) per additional risk allele after adjustment for T2DM risk factors. The gene score in those with no family history of T2DM was 16.02, whereas it was 16.19 in those with one parent with T2DM and it was 16.32 in those with two parents with T2DM (P trend = 0.0004). The C statistic of T2DM risk factors was 0.708 (0.691-0.725) and increased only marginally to 0.714 (0.698-0.731) with the addition of the gene score (P for C statistic change = 0.0052).CONCLUSIONT2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.
    Diabetes care 04/2013; · 7.74 Impact Factor
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    ABSTRACT: We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot, using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P=1.4×10(-7)) and replicated convincingly (P=3.9×10(-5)) in 798 cases and 2931 controls (per allele OR=1.27 in replication cohort, P=7.7×10(-11) in combined populations). SNPs in the glypican 5 gene (GPC5) on chromosome 13q32 were also associated (P=1.7×10(-7)) and replicated convincingly (P=1.2×10(-5)) in 789 cases and 2927 controls (per allele OR=1.31 in replication cohort, P=3.03×10(-11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of Tetralogy of Fallot.
    Human Molecular Genetics 01/2013; · 7.69 Impact Factor
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    ABSTRACT: AIMS: Previous genome-wide linkage analysis has suggested that chromosomal region 17p13.3 may harbour genes influencing left ventricular mass (LVM) in man. To date, the genetic factors accounting for LVM variability remain largely unknown but a non-coding RNA gene within this region, micro-RNA 22 (miR-22), has been implicated in cardiac hypertrophy and heart failure in animal models. We thus investigated the relationship between common genetic polymorphisms surrounding miR-22 and left ventricular mass in a family-based association study. METHODS AND RESULTS: We studied a cohort of 255 families comprising 1,425 individuals ascertained via a hypertensive proband. Ten single nucleotide polymorphisms which together tagged common genetic variation surrounding the miR-22 gene were genotyped. There was evidence of association between the rs7223247 polymorphism, which lies within the 3'UTR of a gene of unknown function, TLCD2, immediately downstream from miR-22, and left ventricular mass determined by Sokolow-Lyon voltage (Bonferroni corrected p-value = 0.038). The T allele at rs7223247 was associated with an 0.272 standard deviation higher Sokolow-Lyon voltage. Genotype was responsible for ∼1% of the population variability in LVM. CONCLUSIONS: Genotype at the rs7223247 polymorphism affects left ventricular mass determined by Sokolow-Lyon voltage. The neighbouring genes miR-22 and TLCD2 are strong candidates to account for this observation.
    PLoS ONE 01/2013; 8(1):e55061. · 3.73 Impact Factor
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    ABSTRACT: AIMS: Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement. METHODS AND RESULTS: Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = -0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE. CONCLUSION: Concentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement.
    European heart journal cardiovascular Imaging. 11/2012;
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    ABSTRACT: Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.
    The American Journal of Human Genetics 10/2012; · 11.20 Impact Factor

Publication Stats

2k Citations
774.82 Total Impact Points


  • 2014
    • The University of Manchester
      Manchester, England, United Kingdom
  • 2002–2014
    • Newcastle University
      • • Institute of Genetic Medicine
      • • School of Mathematics and Statistics
      • • Institute for Ageing and Health
      Newcastle-on-Tyne, England, United Kingdom
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
  • 2009
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
  • 2008
    • Groote Schuur Hospital
      Kaapstad, Western Cape, South Africa
  • 2004–2008
    • University of Cambridge
      • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
  • 2002–2008
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • Cardiothoracic Centre
      Newcastle-on-Tyne, England, United Kingdom
  • 2001–2005
    • University of Oxford
      • • Department of Cardiovascular Medicine
      • • Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)
      • • Wellcome Trust Centre for Human Genetics
      Oxford, ENG, United Kingdom