Submission Details

DNAJB11 is located on chromosome 3q27 and encodes the DnaJ heat shock protein family (Hsp40) member B11. DNAJB11 is a soluble glycoprotein of the endoplasmic reticulum and acts as a co-factor of binding immunoglobulin protein (BiP) for the proper folding assembly, trafficking, and degradation of membrane or secretory proteins. DNAJB11 is expressed in all human tissues, with the highest expression in the pancreas and testis (PMID: 10827079).
Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their inheritance pattern AND phenotypic spectrum. Therefore, autosomal recessive ciliopathy has been curated separately. To date, two cases have reported biallelic inheritance of DNAJB11 variants in individuals with an earlier onset, more severe phenotype than individuals with a monoallelic variant (PMID: 34177435, 33129895). DNAJB11 was first reported in relation to autosomal dominant polycystic kidney disease(ADPKD) in 2018 (Cornec-Le Gall et al., PMID: 29706351). The mechanism of pathogenicity appears to be reduction of function. The reported patients presented with multiple, small, bilateral kidney cysts, non-enlarged kidneys, kidney failure onset after the sixth decade of life, and approximately half of patients with at least one liver cyst. Other features have been inconsistently reported, including gout and interstitial fibrosis, kidney stones, intracranial aneurysm, thoracic aortic dilation, and carotid artery dissection (PMID: 29706351, 32631624, 35664268, 32775842). At least 17 unique variants (missense, nonsense, frameshift) have been reported in 29 probands within four publications (PMID: 29706351, 32631624, 35664268, 32775842) included in this curation. Variants in this gene segregated with disease in 56 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by experimental evidence in expression studies and animal models. Expression level evidence in human renal cortical tubular epithelial cells showed that PC1 membrane expression in DNAJB11 null cells was less than half of what was seen in wildtype cells (PMID: 29706351). This suggests that DNAJB11-related disease leads to impaired maturation of PC1, which would lead to cystogenesis. A Dnajb11-null mouse was created and resulted in live-born mice at a lower-than-expected Mendelian ratio which developed an atypical polycystic kidney phenotype (PMID: 37332102). These cell lines also noted a reduced level of mature PC1 and an increased level of immature, full length PC1, suggesting that DNAJB11-null cells impair cleavage of PC1. A conditional mouse model for Dnajb11 inactivation was also created and revealed PC1 dosage-dependent kidney cyst development. A total of 2.5/6 pts. for experimental evidence was reached. In summary, there is Definitive evidence supporting the relationship between DNAJB11 and ADPKD. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date October 25, 2023 (SOP Version 9).