Recurrent 17q12 microduplications contribute to renal disease but not diabetes.

BACKGROUND: 17q12 microdeletion and microduplication syndromes present as overlapping, multisystem disorders. We assessed the disease phenotypes of individuals with 17q12 CNV in a population-based cohort. METHODS: We investigated 17q12 CNV using microarray data from 450 993 individuals in the UK Biobank and calculated disease status associations for diabetes, liver and renal function, neurological and psychiatric traits. RESULTS: We identified 11 17q12 microdeletions and 106 microduplications. Microdeletions were strongly associated with diabetes (p=2×10-7) but microduplications were not. Estimated glomerular filtration rate (eGFR mL/min/1.73 m2) was consistently lower in individuals with microdeletions (p=3×10-12) and microduplications (p=6×10-25). Similarly, eGFR <60, including end-stage renal disease, was associated with microdeletions (p=2×10-9, p<0.003) and microduplications (p=1×10-9, p=0.009), respectively, highlighting sometimes substantially reduced renal function in each. Microduplications were associated with decreased fluid intelligence (p=3×10-4). SNP association analysis in the 17q12 region implicated changes to HNF1B as causing decreased eGFR (NC_000017.11:g.37741642T>G, rs12601991, p=4×10-21) and diabetes (NC_000017.11:g.37741165C>T, rs7501939, p=6×10-17). A second locus within the region was also associated with fluid intelligence (NC_000017.11:g.36593168T>C, rs1005552, p=6×10-9) and decreased eGFR (NC_000017.11:g.36558947T>C, rs12150665, p=4×10-15). CONCLUSION: We demonstrate 17q12 microdeletions but not microduplications are associated with diabetes in a population-based cohort, likely caused by HNF1B haploinsufficiency. We show that both 17q12 microdeletions and microduplications are associated with renal disease, and multiple genes within the region likely contribute to renal and neurocognitive phenotypes.

IgA Nephropathy Genetic Risk Score to Estimate the Prevalence of IgA Nephropathy in UK Biobank.

BACKGROUND: IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB). METHODS: We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB. RESULTS: The IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23-4.38) than in controls (3.98; 3.97-3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02-4.06) than UKBB controls (3.98; 3.97-3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02-4.13) versus (3.98; 3.97-3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB. CONCLUSIONS: We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts.

A novel approach to Junior Doctor Induction: A near-peer based curriculum developed and delivered by outgoing Foundation year doctors.

There is a 4-12% increase in mortality in the month following the start of Foundation Year 1 doctors (FY1s) in the UK. In 2012 the National Health Service announced a compulsory shadowing period for FY1s, aiming to increase familiarity with the environment in which the FY1 would be commencing work. There is no national curriculum of the content for this shadowing period and evidence suggests variable content of induction programmes across the UK. Our project aimed to provide a near-peer induction, based on needs previously identified by a national survey and outgoing FY1s' experiences. The day consisted of expert-led lectures, interactive practical sessions delivered by outgoing FY1s, and simulated tasks within the clinical environment where they were about to commence work. The day was evaluated by questionnaires distributed to participants before and after the induction to measure whether there was a change in the perceived confidence of the FY1s in different aspects of their role. There was a 61% improvement in familiarity of equipment and knowing how to request investigations. Confidence levels increased by 45% and 28% in prescribing insulin and intravenous fluids, respectively. There was a 9% improvement in feeling adequately prepared to recognise the critically ill patient. Confidence was high in prescribing intravenous fluids (72% pre-induction and 100% post-induction) and simple analgesics (94% pre-induction and 96% post-induction). The induction day improved self-perceived confidence in all measured areas. The largest increase was in the area given most focus during the day - knowledge of the environment. Combining factual content with orientation of the environment increases confidence for new FY1s. Teaching by outgoing FY1s provides insight into what the job entails. We recommend this style of induction to maximise preparedness within a limited time frame.

Hepatic hydrothorax in the absence of ascites.

A previously well 66-year-old woman presented with a recurrent transudative right-sided pleural effusion. A nodular liver with coarse echotexture was demonstrated on ultrasound and subsequent MRI found hepatocellular carcinoma. In the absence of cardiopulmonary disease and significant protein uria, the recurrent pleural effusion was presumed to be hepatic hydrothorax despite the absence of ascites or other clinical features of chronic liver disease. The patient is currently awaiting liver transplantation.