Abstract: SA-PO606
Clinical Gout Separates ADTKD-UMOD from ADTKD-MUC1 in a Large International Registry
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Olinger, Eric Gregory, University of Zurich, Zurich, Switzerland
- Kidd, Kendrah O., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Greka, Anna, Harvard Medical School, Boston, Massachusetts, United States
- Kmoch, Stanislav, Institute of Inherited Metabolic Disorders, Prague, Czechia
- Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Devuyst, Olivier, University of Zurich, Zurich, Switzerland
Background
Autosomal dominant tubulointerstitial kidney diseases (ADTKD) comprise a group of rare disorders characterized by progressive CKD with interstitial fibrosis and tubular atrophy. ADTKD is genetically heterogeneous: mutations in UMOD are mainly involved but MUC1, HNF1B and REN have also been associated. Despite a recent gene-based disease ontology, clinical characteristics and diagnostic criteria of various ADTKD subgroups remain to be defined.
Methods
In an international effort, 463 families diagnosed with ADTKD were included in a comprehensive registry. Index cases were screened for UMOD mutations, followed by MUC1, HNF1B and REN mutations in UMOD-negative families.
Results
We detected mutations in UMOD in 181 families (39.1%). Among the UMOD-negative families, 20.3% screened positive for MUC1, 12.5% positive for HNF1B and 1.8% positive for REN mutations. 107 mutations were detected in UMOD, all missense except 7 small indels, with 90% clustering in exon 3 and 56% involving cysteine residues. All MUC1 families displayed cytosine insertion in the VNTR region. Point mutations, small indels and large genomic rearrangements were reported in HNF1B. Clinical gout was more prevalent in ADTKD-UMOD cases compared to ADTKD-MUC1 (58% vs. 17% of cases respectively, p<0.0001; PPV: 0.86) with an earlier age of onset (29.0±12.7 vs. 43.3±14.2 years; p<0.0001). A family history (FH) of CKD and gout was reported in 66% of ADTKD-UMOD cases contrasting with a predominant FH of isolated CKD in 84% of ADTKD-MUC1. FH of CKD with gout separates ADTKD-UMOD from ADTKD-MUC1 (p<0.0001; PPV: 0.92) in this cohort.
Conclusion
Mutations in UMOD and MUC1 are the leading genetic causes for ADTKD. Personal or familial history of clinical gout and early age of gout onset are specifically associated with ADTKD-UMOD inside this group of disorders. This international registry will help to identify modifying genes and biomarkers in ADTKD subgroups and to test future interventions.