#1154 Detecting MUC1 VNTR variants using VNtyper in Irish patients

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Abstract Background and Aims Autosomal dominant tubulointerstitial kidney disease MUC1 (ADTKD-MUC1) is a rare genetic cause of renal impairment resulting from specific frameshift variants in the coding variable number tandem repeats (VNTR) of the MUC1 gene. ADTKD-MUC1 is characterized by progressive loss of kidney function leading to ESRD, histological evidence of tubular atrophy and interstitial fibrosis and an autosomal dominant inheritance pattern. Due to its repetitive nature and high GC content, there is great difficulty in detecting pathogenic variants in MUC1 VNTR using common methods such as exome or targeted sequencing. VNtyper is a new bioinformatics tool designed to genotype MUC1 VNTR using short-read sequencing data for reliable detection of pathogenic variants in this region. In this study, we used VNtyper for analysing exome data of large cohort of Irish renal patients in order to (i) validate its performance, (ii) explore its ability to reanalyse patients with chronic kidney disease (CKD) and (iii) examine the presence of pathogenic MUC1 VNTR variants in other renal disorders such as polycystic kidney disease (PKD). Method Patients were recruited via the Inherited Kidney Disease Clinic at Beaumont Hospital, Dublin, Ireland. Detection of pathogenic variants in MUC1 VNTR was performed by processing and analysing whole exome sequencing (WES) and targeted sequencing (TS) data of the patients using the VNtyper software. The performance of VNtyper was validated by testing samples from diagnosed ADTKD-MUC1 patients (n = 6) whose pathogenic variants were identified previously by the Snapshot method. We tested a cohort of 522 non-cystic CKD patients and 366 cystic kidney disease patients through a systematic scan by VNtyper. Results The VNtyper validated the results of the six ADTKD-MUC1 patients showed that they were all heterozygous carriers of a same pathogenic frameshift insertion in MUC1 VNTR. These findings are identical to the results of the Snapshot test conducted independently for these patients and are a complete replication of them. Among the 522 CKD patients reanalysed by VNtyper, four had heterozygous pathogenic frameshift insertions in the MUC1 VNTR. Clinically, the symptoms of these patients are consistent with those of ADTKD-MUC1. Among the 366 cystsic kidney disease patients screened by the VNtyper, four were found to carry heterozygous frameshift insertions in the MUC1 VNTR. Conclusion Until now, for many renal patients, their genomic testing for pathogenic variants in the MUC1 VNTR was difficult. The results of this study strengthen the reliability of the use of VNtyper and demonstrate its great potential for reanalysing short-read sequencing data for the diagnosis of ADTKD-MUC1 patients and for exploring the possible role of MUC1 in other kidney disorders.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.