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.

[1]  Boe,et al.  Genetic insights into biological mechanisms governing human ovarian ageing , 2021, Nature.

[2]  F. Scolari,et al.  Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease , 2020, Kidney international reports.

[3]  Gonçalo Abecasis,et al.  Computationally efficient whole-genome regression for quantitative and binary traits , 2020, Nature Genetics.

[4]  J. Tyrrell,et al.  Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates. , 2020, American journal of human genetics.

[5]  Sang Soo Kim,et al.  Differential Urinary Proteome Analysis for Predicting Prognosis in Type 2 Diabetes Patients with and without Renal Dysfunction , 2020, International journal of molecular sciences.

[6]  J. Tyrrell,et al.  A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function , 2020, Diabetes.

[7]  Ryan L. Collins,et al.  The mutational constraint spectrum quantified from variation in 141,456 humans , 2020, Nature.

[8]  2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2020 , 2019, Diabetes Care.

[9]  A. Ekici,et al.  Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome? , 2019, Prenatal diagnosis.

[10]  Y. Horikawa,et al.  Clinical manifestations of a sporadic maturity-onset diabetes of the young (MODY) 5 with a whole deletion of HNF1B based on 17q12 microdeletion. , 2019, Endocrine journal.

[11]  P. Donnelly,et al.  The UK Biobank resource with deep phenotyping and genomic data , 2018, Nature.

[12]  D. Pilz,et al.  Chromosome 17q12 duplications: Further delineation of the range of psychiatric and clinical phenotypes , 2018, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[13]  A. Hattersley,et al.  Comment on Dubois-Laforgue et al. Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects. Diabetes Care 2017;40:1436–1443 , 2017, Diabetes Care.

[14]  T. Tuomi,et al.  Biliary Anomalies in Patients With HNF1B Diabetes , 2017, The Journal of clinical endocrinology and metabolism.

[15]  J. Coste,et al.  Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects , 2017, Diabetes Care.

[16]  L. Sunde,et al.  17q12 deletion and duplication syndrome in Denmark—A clinical cohort of 38 patients and review of the literature , 2016, American journal of medical genetics. Part A.

[17]  A. Hattersley,et al.  Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder , 2016, Kidney international.

[18]  F. Cunningham,et al.  The Ensembl Variant Effect Predictor , 2016, Genome Biology.

[19]  T. Seeman,et al.  Hepatic phenotypes of HNF1B gene mutations: a case of neonatal cholestasis requiring portoenterostomy and literature review. , 2015, World journal of gastroenterology.

[20]  A. Hattersley,et al.  HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum , 2015, Nature Reviews Nephrology.

[21]  Jennifer S. Woo,et al.  Duodenal atresia in 17q12 microdeletion including HNF1B: A new associated malformation in this syndrome , 2014, American journal of medical genetics. Part A.

[22]  P. Rossini,et al.  Clinical, neurophysiological and pathological findings of HNPP patients with 17p12 deletion: A single-centre experience , 2014, Journal of the Neurological Sciences.

[23]  A. Jehle,et al.  Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2. , 2014, American journal of physiology. Renal physiology.

[24]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[25]  Swaroop Aradhya,et al.  An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities , 2011, Genetics in Medicine.

[26]  P. Calvas,et al.  A 17q12 chromosomal duplication associated with renal disease and esophageal atresia. , 2011, European journal of medical genetics.

[27]  A. Gharavi,et al.  HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort , 2011, Pediatric Nephrology.

[28]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[29]  J. Ioannidis,et al.  STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement , 2009, PLoS medicine.

[30]  A. Hattersley,et al.  Hepatocyte nuclear factor-1beta gene deletions--a common cause of renal disease. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[31]  H. Mefford,et al.  Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. , 2007, American journal of human genetics.

[32]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[33]  M. Jadoul,et al.  Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. , 2005, Diabetes.

[34]  A. Hattersley,et al.  Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. , 2001, American journal of human genetics.

[35]  T. Frayling,et al.  Mutations in the Hepatocyte Nuclear Factor–1α Gene Are a Common Cause of Maturity-Onset Diabetes of the Young in the U.K. , 1997, Diabetes.

[36]  R. Tattersall.  Mild familial diabetes with dominant inheritance. , 1974, The Quarterly journal of medicine.