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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. [ABSTRACT FROM AUTHOR]

Background Monogenic disorders are estimated to account for 10%-12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin (UMOD) variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant. Methods Probands from 12 apparently unrelated pedigrees with a family history of kidney failure within a geographically contiguous UK region were shown to be heterozygous for a pathogenic variant of UMOD c.278_289delTCTGCCCCGAAG insCCGCCTCCT. Results A total of 88 clinically affected individuals were identified, all born in the UK and of white British ethnicity. 20 other individuals with the variant were identified in the UK 100,000 Genomes (100K) Project and 9 from UK Biobank (UKBB). A common extended haplotype was present in 5 of the UKBB individuals who underwent genome sequencing which was only present in <1 in 5000 of UKBB controls. Significantly, rare variants (<1 in 250 general population) identified within 1 Mb of the UMOD variant by genome sequencing were detected in all of the 100K individuals, indicative of an extended shared haplotype. Conclusion Our data confirm a likely founder UMOD variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry. [ABSTRACT FROM AUTHOR]

Background Fabry disease is an X-linked lysosomal storage disorder resulting from deficiency of the alpha-galactosidase A enzyme leading to accumulation of globotriaosylceramide in multiple organ sites with prominent cardiovascular and renal involvement. Global prevalence estimates of Fabry disease based on clinical ascertainment range from 1 in 40 000 to 1 in 170 000. We aimed to determine the prevalence of Fabry disease-causing variants in UK Biobank. Methods We sought GLA gene variants in exome sequencing data from 200 643 individuals from UK Biobank. We used ACMG/AMP guidelines (American College of Medical Genetics/Association for Molecular Pathology) to classify pathogenicity and compared baseline biomarker data, hospital ICD-10 (International Classification of Diseases version-10) codes, general practitioner records and self-reported health data with those without pathogenic variants. Results We identified 81 GLA coding variants. We identified eight likely pathogenic variants on the basis of being rare (<1/10 000 individuals) and either previously reported to cause Fabry disease, or being protein-truncating variants. Thirty-six individuals carried one of these variants. In the UK Biobank, the prevalence of likely pathogenic Fabry disease-causing variants is 1/5732 for late-onset disease-causing variants and 1/200 643 for variants causing classic Fabry disease. Conclusion Fabry disease-causing GLA variants are more prevalent in an unselected population sample than the reported prevalence of Fabry disease. These are overwhelmingly variants associated with later onset. It is possible the prevalence of later-onset Fabry disease exceeds current estimates. [ABSTRACT FROM AUTHOR]