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. 2023 May;60(5):491-497.
doi: 10.1136/jmg-2022-108615. Epub 2022 Sep 15.

Recurrent 17q12 microduplications contribute to renal disease but not diabetes

Stuart Cannon  1 , Rhian Clissold  2 , Kittiya Sukcharoen  3 , Marcus Tuke  3 , Gareth Hawkes  3 , Robin N Beaumont  3 , Andrew R Wood  3 , Mark Gilchrist  3 , Andrew T Hattersley  3 , Richard A Oram  3 , Kashyap Patel  3 , Caroline Wright  3 , Michael N Weedon  3
Affiliations

Recurrent 17q12 microduplications contribute to renal disease but not diabetes

Stuart Cannon et al. J Med Genet. 2023 May.

Abstract

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.

Keywords: diabetes mellitus; endocrinology; nephrology.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
17q12 genomic region highlighting segmental microduplications, microdeletions and microduplications identified in this study. Only the unique detectable regions for microdeletions (n=6) and microduplications (n=50), based on CNV calling, are shown. The remaining identified microdeletions (n=5) and microduplications (n=56) share breakpoints, with one which is plotted.
Figure 2
Figure 2
Forest plots of 17q12 microdeletions and microduplication disease associations in the UK Biobank. Left panel: binary traits; right panel: inverse normalised continuous traits. Note that SD below 0 represents negative associations. ACR, urinary albumin to creatinine ratio; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C reactive protein; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GGT, gamma glutamyl transferase; HbA1c, glycated haemoglobin.
Figure 3
Figure 3
LocusZoom plots of GWAS SNP testing: (A) diabetes, (B) alanine aminotransferase, (C) estimated glomerular filtration rate and (D) fluid intelligence. The red vertical box indicates HNF1B location. The green dashed line indicates genome-wide significance at 1×10−8.
See this image and copyright information in PMC

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