MO032: Autosomal dominant tubulointerstitial kidney diseases (ADTKD): single center cohort
Authors: Jorge Sofia , Silveira Catarina , Rodrigues Márcia , Godinho Iolanda , Nogueira Estela , António Lopes José 
Published: May 2022

BACKGROUND AND AIMS

ADTKD represents a recently described group of kidney diseases, characterized by chronic interstitial nephritis (CIN), in most cases hereditary, with an autosomal dominant inheritance pattern, subclassified according to its genetic cause, when identified. Mutations in UMOD, MUC1, REN and HNF1B genes have been implicated in their pathogenesis. Recent molecular diagnostic technologies, such as next-generation sequencing (NGS), and particularly the use of restriction and snapshot method for the detection of a cytosine insertion on the coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1, have allowed the nephrologists to diagnose renal diseases of previously unknown cause, with a real prevalence probably underestimated. We present the cohort of patients identified with ADTKD in the nephrogenetics clinic from the nephrology department of our hospital from 2015 to 2021.

METHOD

patients with CKD of unknown etiology and renal phenotype suggesting chronic interstitial nephritis (bland urine analysis, hyperuricemia and/or anemia unrelated to the degree of chronic kidney disease, hypo/hypercalemia, acidemia, urinary concentration defects, absent hypertension and renal cysts), especially with a family history of similar CKD, were referred for the nephrogenetics clinic and ADTKD was investigated. In these cases, we performed a genetic study of ADTKD by the following steps: (1) UMOD, REN, HNF1 B mutations studied through next-generation sequencing (NGS); (2) if negative, search for the insertion of a single cytosine of the repeat unit comprising the extremely long (∼1.5–5 kb), GC-rich (&gt;80%) coding VNTR sequence in the MUC1 gene encoding mucin 1 (see Kirby et al. 2013). It is used a restriction and  snapshot method. (3) If negative, search for HNF1B Large deletion, detected by multiplex ligation-dependent probe amplification (MLPA) (kit P241-D2, MRC-Holland).

Pre-genetic counseling was performed by the nephrologist and post-genetic counseling was performed by the nephrologist and geneticist, namely to proceed with family screening of potentially affected family members when a pathogenic mutation was identified or when segregation studies were necessary.

RESULTS

A total of 30 families were studied and a confirmed genetic diagnosis was obtained in 10 (30%), allowing the identification of 29 patients with ADTKD; the mutations identified were in MUC1 in four families (13 patients), UMOD in four families (11 patients), HNF 1 beta (1 family, 4 patients) and REN: one patient with a phenotype compatible with ADTKD but with a genotype compatible with renal tubular dysgenesis (two mutations in REN gene from each of the parents). Three families are still under study: two families are being studied with segregation studies to evaluate the pathogenicity of mutations in UMOD (1 family) and HNF1B (1 family), and one family with a phenotype of ADTKD (three young patients with positive family history) with negative results for mutations in ADTKD genes is in study, pursuing with WES. If positive results are obtained for these three families, the percentage of families identified through the use of this protocol will increase to 43.3% of the families studied through this model.

CONCLUSION

In our cohort, a genetic diagnosis was established in 30% of the families studied. MUC 1 and UMOD are the most prevalent genes implicated in ADTKD at our center, similar to what has been reported in other cohorts of ADTKD.

Given the rarity of these diseases and the fact that they require specific molecular techniques for accurate diagnosis, we believe that nephrogenetics clinics with dedicated nephrologists and geneticists in straight cooperation are critical for accurate diagnosis.