DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature.

Keywords: ADPKD; DNAJB11; atypical; genetics; mutation.

Figure 1

Imaging scans (A–E). (A) Patient 1: MRI (05/2023); (B) Patient 2: MRI (12/2022); (C) Patient 3: CT (03/2023); (D) Patient 4: CT (05/2023); (E) Patient 5: MRI (07/2020).

Figure 2

The low resolution shows severe interstitial fibrosis with slightly less tubular atrophy, several globally sclerosed glomeruli, and moderate to severe intima fibrosis of an interlobular artery (blue arrow). In addition, a mild limpho-monocytic infiltration with frequent macrophages in scared areas and one tubular cyst (green arrow) could be observed. Trichrome, magnification ×400.

Figure 3

Family trees (A–D). (A) The first family presented two brothers (generation II, subjects 1 and 3) affected by the DNAJB11 variant c.716 T>G (p. Leu239Ter), while their mother presented a non-diagnosed CKD. (B) In the second family, only the proband (generation II, subject 1) was diagnosed with the DNAJB11 variant c.134A>G (p.Tyr45Cys), while his siblings were not available for the family segregation. (C) In this third family, two cousins presented the DNAJB11 variant c.456+3_456+6del. Subject 2 of generation II also presented multicystic kidneys, although she never underwent genetic testing. Subject 3 of generation II did not show any signs or symptoms of CKD as she died at a young age. Finally, subject 1 of the generation I also presented CKD. (D) In the last family, subject 1 of generation II presented the DNAJB11 variant c.499C>T (p.Arg167Trp), her father presented CKD, but he was never evaluated with genetic testing.