Author(s): Paes de Faria, Vitória ; Dias, Joana ; Falcão Reis, Cláudia ; Santos, Sofia ; Gomes, Ana Marta
Date: 2026
Origin: Portuguese Kidney Journal (PKJ)
Subject(s): Adult; Ciliopathies/genetics; Genetic Testing; Kidney Diseases, Cystic/genetics; Kidney Failure, Chronic/ genetics
Nephronophthisis is the most common monogenic cause of chronic kidney failure within the first three decades of life. Adult-onset disease remains largely underdiagnosed because of its subtle and nonspecific clinical presentation. We report two families with adult-onset chronic kidney disease (CKD), of undetermined aetiology who were subsequently diagnosed with a homozygous pathogenic variant in TTC21B, c.626C>T (p.Pro209Leu) associated with nephronophthisis type 12. Pathogenic variants in TTC21B are associated with heterogenous renal phenotypes, including both tubulointerstitial and glomerular involvement, and are rarely reported in adult patients. With the increasing availability and comprehensive genetic testing, a paradigm shift has occurred in the diagnostic approach to CKD of unknown origin in young adults. Our findings suggest that TTC21B-nephronophthisis represents an underrecognized cause of end-stage kidney disease, characterized by combined tubulointerstitial fibrosis and focal segmental sclerosis. These cases underscore the importance of pursuing a definitive etiological diagnosis in young adults with CKD, given the significant implications for prognosis, clinical management and long-term genetic counselling.
