CONCENTRATION ISSUES IN THE U.S. BEEF SUBSECTOR

Industrial Organization, Livestock Production/Industries,

Combinatorial Conflicting Homozygosity (CCH) analysis enables the rapid identification of shared genomic regions in the presence of multiple phenocopies.

The ability to identify regions of the genome inherited with a dominant trait in one or more families has become increasingly valuable with the wide availability of high throughput sequencing technology. While a number of methods exist for mapping of homozygous variants segregating with recessive traits in consanguineous families, dominant conditions are conventionally analysed by linkage analysis, which requires computationally demanding haplotype reconstruction from marker genotypes and, even using advanced parallel approximation implementations, can take substantial time, particularly for large pedigrees. In addition, linkage analysis lacks sensitivity in the presence of phenocopies (individuals sharing the trait but not the genetic variant responsible). Combinatorial Conflicting Homozygosity (CCH) analysis uses high density biallelic single nucleotide polymorphism (SNP) marker genotypes to identify genetic loci within which consecutive markers are not homozygous for different alleles. This allows inference of identical by descent (IBD) inheritance of a haplotype among a set or subsets of related or unrelated individuals

A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen

BACKGROUND: Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts. METHODS: We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses. RESULTS: We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the C-terminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested. CONCLUSIONS: Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated with HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the α1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans

A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen.

BACKGROUND: Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts. METHODS: We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses. RESULTS: We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the C-terminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested. CONCLUSIONS: Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated with HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the α1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans

Genetic testing can resolve diagnostic confusion in Alport syndrome

Alport syndrome (AS) is a familial glomerular disorder resulting from mutations in the genes encoding several members of the type IV collagen protein family. Despite advances in molecular genetics, renal biopsy remains an important initial diagnostic tool. Histological diagnosis is challenging as features may be non-specific, particularly early in the disease course and in females with X-linked disease. We present three families for whom there was difficulty in correctly diagnosing AS or thin basement membrane nephropathy as a result of misinterpretation of non-specific and incomplete histology. We highlight the importance of electron microscopy and immunofluorescence in improving diagnostic yield and also the hazard of interpreting a descriptive histological term as a diagnostic label. Molecular genetic testing allows a definitive diagnosis to be made in index patients and at-risk family members

Incidence of end-stage renal disease in the Turkish-Cypriot population of Northern Cyprus: a population based study.

BACKGROUND: This is the first report of the incidence and causes of end-stage renal disease (ESRD) of the Turkish-Cypriot population in Northern Cyprus. METHODS: Data were collected over eight consecutive years (2004-2011) from all those starting renal replacement therapy (RRT) in this population. Crude and age-standardised incidence at 90 days was calculated and comparisons made with other national registries. We collected DNA from the entire prevalent population. As an initial experiment we looked for two genetic causes of ESRD that have been reported in Greek Cypriots. RESULTS: Crude and age-standardised incidence at 90 days was 234 and 327 per million population (pmp) per year, respectively. The mean age was 63, and 62% were male. The age-adjusted prevalence of RRT in Turkish-Cypriots was 1543 pmp on 01/01/2011. The incidence of RRT is higher than other countries reporting to the European Renal Association - European Dialysis and Transplant Association, with the exception of Turkey. Diabetes is a major cause of ESRD in those under 65, accounting for 36% of incident cases followed by 30% with uncertain aetiology. 18% of the incident population had a family history of ESRD. We identified two families with thin basement membrane nephropathy caused by a mutation in COL4A3, but no new cases of CFHR5 nephropathy. CONCLUSIONS: This study provides the first estimate of RRT incidence in the Turkish-Cypriot population, describes the contribution of different underlying diagnoses to ESRD, and provides a basis for healthcare policy planning

Childhood cognitive ability and smoking initiation, relapse and cessation throughout adulthood: Evidence from two British cohort studies

Aims  To test the relationship between early cognitive ability and major changes in smoking habits across adulthood, and test whether educational attainment mediates these associations.  Design  Prospective observational study to examine the link between cognitive ability and smoking initiation, relapse and cessation at multiple time-points throughout adulthood in a pooled analysis of two cohorts.  Setting  Great Britain 1981–2013.  Participants  A total of 16 653 participants from two British cohorts; 7191 from the 1970 British Cohort Study (BCS) and 9462 from the 1958 National Child Development Study (NCDS). Participants were 52.9% female and 27.3% were smokers, 24.8% were ex-smokers and 47.9% reported never smoking.  Measurements  Cognitive ability was assessed at age 10years in the BCS and 11years in the NCDS. Outcomes were smoking initiation, relapse and cessation derived from changes in smoking status observed across five time-points between ages 26–42 in the BCS and six time-points between ages 23–55 in the NCDS. Educational attainment was examined as a mediating variable. Controls were age, gender, social class, self-control, psychological distress, parental smoking and a study indicator (BCS/NCDS).  Findings  In adjusted regression models, a 1 standard deviation increase in cognitive ability predicted a 0.5 percentage point (95% CI=−0.9 to −0.1) reduced probability of smoking and a 2.9 percentage point (95% CI=2.1–3.7) higher probability of smoking cessation throughout adulthood, but did not change the likelihood of smoking relapse significantly. Differences in educational attainment explained approximately half the association between childhood cognitive ability and smoking initiation/cessation.  Conclusions  Lower cognitive ability, measured in childhood before smoking is initiated, appears to predict a higher likelihood of taking up smoking and a lower likelihood of quitting in adulthood. Educational attainment appears to mediate this effect: children with higher cognitive ability tend to become more highly educated adults which, in turn, predicts lower rates of smoking initiation and increased rates of smoking cessation

Individual student characteristics and attainment in pre-registration physiotherapy : a retrospective multi-site cohort study

Introduction: Worldwide there is a desire to diversify the physiotherapy workforce. However, limited research indicates that some student characteristics linked to under-representation in pre-registration physiotherapy education have lower attainment and greater attrition. This study explored the relationship between individual characteristics and success of students in pre-registration physiotherapy education within South East England. Design: A retrospective multi-site cohort study including pre-registration physiotherapy programmes in the South East of England. Anonymised data included background information (age, gender, ethnicity, socio-economic status) and outcomes (assessment marks, type of award and classification of degree). Analysis involved Bayesian regression models and ordinal logistic regression to examine the association of student characteristics on outcomes. Results: Data from 1851 student records were collected from four institutions. There were significantly lower assessment scores for Asian (-11.1% 95% CI: -13.1 to -9.2), Black (-7.1%, 95% CI: -9.7 to -4.5) and Other/Mixed ethnicity groups (-4.7%, 95% CI: -7.1 to -2.4), most notable in clinical and observed assessments, compared to their White British colleagues. All BME groups also demonstrated worse odds for a one step lower overall award or no award (Black OR: 3.35, Asian OR: 3.97, Other OR: 2.03). Associations of learning disability, age and non-traditional entry routes with assessment scores and/or degree classification were also noted. Conclusion: These findings suggest significant attainment gaps in pre-registration physiotherapy education in this specific geographical region, particularly for non-White ethnic and disability groups. The association with assessment type challenges educators to look beyond a purely student deficit model to explore all factors that may lead to inequality. © 2017 The Authors.Health Education North West London (HENWL) grant (P063)