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The following is a summary of “Systematic Screening of ADTKD-MUC1 27dupC Pathogenic Variant through Exome Sequencing,” published in the September 2024 issue of Nephrology by Bensouna et al. 

The MUC1 gene causes autosomal dominant tubulointerstitial kidney disease (ADTKD), leading to CKD. Traditional exome sequencing struggles to detect MUC1 variants due to the variable number of tandem repeats (VNTR) in exon 2. 

Researchers conducted a retrospective study and found that fast read filtering with VNTR genotyping enables screening of the 27dupC MUC1 variant from exome data. 

They validated the pipeline in 33 participants with a known MUC1 variant and 54 MUC1-negative controls. Retrospective analysis was done on 3,512 adults with nephropathy (January 2019 to October 2023), followed by prospective validation in 825 participants (from November 2023). 

The results showed that SharkVNTyper identified MUC1 variants in 32 of 33 participants and excluded them in all 54 negative controls (sensitivity of 97%, specificity of 100%). The Shark tool was integrated with VNTyper and reduced running time from 6-12 hours to 5-10 minutes per sample, enabling both retrospective and prospective analysis. In the retrospective cohort, SharkVNTyper identified 23 additional positive cases that were previously missed; 18 were confirmed to have the MUC1 27dupC mutation by Snapshot PCR. In the prospective cohort of 825 CKD cases, 13 positive cases were found, with 12 confirmed by PCR. Of the 63 participants (1.4% of 4,653) with confirmed ADTKD-MUC1, comprehensive diagnoses were available for 24. The median age of kidney failure was 50 years; 38% had bilateral kidney cysts, 8% had early-onset gout, and 58% had hypertension. 

Investigators concluded that SharkVNTyper enabled screening of MUC1 VNTR regions from exome data and improved 27dupC variant detection. 

Source: journals.lww.com/jasn/abstract/9900/systematic_screening_of_adtkd_muc1_27dupc.426.aspx