ReNU Syndrome due to a de novo RNU4-2 Variant as a Novel Genetic Cause of Proteinuria

Proteinuria has been linked to several genetic disorders, providing valuable insights into its pathophysiology. ReNU syndrome, a recently described condition caused by heterozygous variants in the RNU4-2 gene, is characterized by intellectual disability, microcephaly, and multisystemic features. Kidney involvement has been reported exclusively as anatomical abnormalities. Here, we presented a girl with isolated proteinuria and ReNU syndrome. Her prenatal history was notable for a small head circumference and reduced brain hemispheres. She was referred to our clinic at 3 months of age for isolated proteinuria. Physical examination revealed microsomia, strabismus, and dysmorphic features. Kidney ultrasound was unremarkable, and edema was never observed. A kidney biopsy showed minimal change disease with slight podocyte effacement. Treatment with prednisone was ineffective, and antiproteinuric agents were started. At her last follow-up, at age 16 years, nephrotic-range proteinuria persists with normal kidney function. Genetic testing before 2024 yielded no diagnosis, but whole-genome sequencing analysis later identified a de novo variant in the RNU4-2 gene (n.64_65insT), confirming ReNU syndrome. This case is the first documented report of isolated, persistent proteinuria in ReNU syndrome. We recommend testing for RNU4-2 variants in patients with unexplained proteinuria and syndromic features and suggest regular monitoring for proteinuria in individuals with ReNU syndrome.