• Another tale of structural inequality?

      de Noronha, Nigel; email: nigel.denoronha@manchester.ac.uk (Blackwell Publishing Ltd, 2021-05-21)
    • Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects

      Pagnamenta, Alistair T.; orcid: 0000-0001-7334-0602; Jackson, Adam; Perveen, Rahat; Beaman, Glenda; Petts, Gemma; Gupta, Asheeta; Hyder, Zerin; Chung, Brian Hon‐Yin; orcid: 0000-0002-7044-5916; Kan, Anita Sik‐Yau; Cheung, Ka Wang; et al. (Blackwell Publishing Ltd, 2021-10-11)
      Abstract: Only two families have been reported with biallelic TMEM260 variants segregating with structural heart defects and renal anomalies syndrome (SHDRA). With a combination of genome, exome sequencing and RNA studies, we identified eight individuals from five families with biallelic TMEM260 variants. Variants included one multi‐exon deletion, four nonsense/frameshifts, two splicing changes and one missense change. Together with the published cases, analysis of clinical data revealed ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse‐shoe kidneys (1/12) and renal cysts (1/12) in patients. Three pregnancies were terminated on detection of severe congenital anomalies. Six patients died between the ages of 6 weeks and 5 years. Using a range of stringencies, carrier frequency for SHDRA was estimated at 0.0007–0.007 across ancestries. In conclusion, this study confirms the genetic basis of SHDRA, expands its known mutational spectrum and clarifies its clinical features. We demonstrate that SHDRA is a severe condition associated with substantial mortality in early childhood and characterised by congenital cardiac malformations with a variable renal phenotype.
    • Dominant‐negative pathogenic variant BRIP1 c. 1045G >C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study

      Flaum, Nicola; orcid: 0000-0001-8900-0645; email: nicola.flaum@manchester.ac.uk; van Veen, Elke M.; orcid: 0000-0001-8618-2332; Smith, Olivia; Amico, Stephanie; Newman, William G.; orcid: 0000-0002-6098-9995; Crosbie, Emma J.; Edmondson, Richard; Smith, Miriam J.; orcid: 0000-0002-3184-0817; Evans, D. Gareth (Blackwell Publishing Ltd, 2021-10-07)
      Abstract: BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case‐control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3–444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5–1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2–106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4–12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3–23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3–12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant‐negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant‐negative missense variants may confer higher risks than their loss‐of‐function counterparts.
    • English Devolution and the Covid‐19 Pandemic: Governing Dilemmas in the Shadow of the Treasury

      Warner, Sam; email: samuel.warner@manchester.ac.uk; Richards, David; Coyle, Diane; Smith, Martin J. (Blackwell Publishing Ltd, 2021-04-08)
      Abstract: This article explores the question of devolution in the light of the Covid‐19 pandemic's impact on English local government. Criticism of the government's handling of the crisis is widespread and tends to focus on the highly centralised nature of the British state. Here, we attribute the challenges faced by regional and local government in responding to the pandemic primarily to the asymmetric nature of power relations that characterise financial planning and control mechanisms, devised and overseen by the Treasury. We argue that the ongoing crisis underlines the need for a democratic form of devolution—including further fiscal powers for regional and local government—to support the economic recovery. In a context of increasing fiscal uncertainty, the Treasury should seek to unlock the existing powers of local leaders by reforming centralised budgetary constraints and taking accountability and monitoring mechanisms closer to citizens.
    • Expanding the genotypic spectrum of TXNL4A variants in Burn‐McKeown syndrome

      Wood, Katherine A.; Ellingford, Jamie M.; Thomas, Huw B.; Genomics UK Research Consortium; Douzgou, Sofia; orcid: 0000-0001-8890-7544; Beaman, Glenda M.; Hobson, Emma; Prescott, Katrina; O'Keefe, Raymond T.; orcid: 0000-0001-8764-1289; Newman, William G.; orcid: 0000-0002-6382-4678; email: william.newman@manchester.ac.uk (Blackwell Publishing Ltd, 2021-11-05)
      Abstract: The developmental disorder Burn‐McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre‐messenger RNA splicing factor TXNL4A. Most patients have a loss‐of‐function variant in trans with a 34‐base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258‐3C>G) and a type 1 Δ34 promoter deletion. We show the c.258‐3C>G variant and a previously reported c.258‐2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22 bp repeated motif could be relevant to BMKS aetiology. Finally, our data emphasises the need to analyse the non‐coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation.
    • Introduction: Corbynism and its Aftermath

      Bassett, Lewis; email: lewis.bassett-yerrell@manchester.ac.uk; Gilbert, Jeremy (Blackwell Publishing Ltd, 2021-05-18)
    • “Success” in policy piloting: Process, programs, and politics

      Checkland, Kath; orcid: 0000-0002-9961-5317; email: katherine.checkland@manchester.ac.uk; Hammond, Jonathan; Coleman, Anna; Macinnes, Julie; Mikelyte, Rasa; Croke, Sarah; Billings, Jenny; Bailey, Simon; orcid: 0000-0001-9142-2791; Allen, Pauline (Blackwell Publishing Ltd, 2021-10-25)
      Abstract: Research has demonstrated that pilots contain multiple shifting purposes, not all of which relate to simple policy testing or refinement. Judging the success of policy pilots is therefore complex, requiring more than a simple judgment against declared goals. Marsh and McConnell provide a framework against which policy success can be judged, distinguishing program success from process and political success. We adapt Boven's modification of this framework and apply it to policy pilots, arguing that pilot process, outcomes and longer‐term effects can all be judged in both program and political terms. We test this new framework in a pilot program in the English National Health Service, the Vanguard program, showing how consideration of these different aspects of success sheds light on the program and its aftermath. We consider the implications of the framework for the comprehensive and multifaceted evaluation of policy pilots.