Kidney Week

Abstract: TH-PO0136

Expanding the Spectrum of FOXI1-Related Distal Renal Tubular Acidosis

Session Information

• Integrative Genomics and Multi-Omics in Noncystic Genetic Kidney Disease
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Tischer, Philipp, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany

Philipp Tischer, MD

• Pillai, Joshua, University of California San Diego, La Jolla, California, United States

Joshua Pillai

• van der Ven, Amelie, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany

Amelie van der Ven

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

• Oh, Jun, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany

Jun Oh, MD

• Sayer, John Andrew, University of New Castle, New Castle upon Tyne, United Kingdom

John Andrew Sayer, MBChB, PhD

• Buerger, Florian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany

Florian Buerger, MD, PhD

Background

Distal renal tubular acidosis (dRTA) is a rare disorder of urinary acidification characterized by hyperchloremic metabolic acidosis, nephrocalcinosis, hypokalemia, and growth impairment. Monogenic forms are most commonly caused by pathogenic variants in ATP6V1B1, ATP6V0A4, and SLC4A1. More recently, biallelic variants in FOXI1, encoding a transcription factor essential for intercalated cell differentiation and proton pump regulation, have been implicated in syndromic dRTA with sensorineural hearing loss. To date, only four affected individuals with FOXI1-associated dRTA have been reported.

Methods

We clinically characterized two affected siblings with dRTA and congenital sensorineural hearing loss from a consanguineous family. Biochemical analyses, kidney ultrasonography, and targeted genetic testing were performed in affected and unaffected siblings. Comparative structural modeling of previously reported and newly identified FOXI1 variants was performed using AlphaFold3-predicted FOXI1 structures and resolved FOX family protein–DNA complexes.

Results

The index patient, a 4-year-old boy, presented with early-onset dRTA, congenital bilateral sensorineural hearing loss requiring cochlear implantation, metabolic acidosis, and nephrocalcinosis. His 16-year-old brother had a similar phenotype with congenital hearing loss, nephrocalcinosis, recurrent fractures, and previously diagnosed dRTA. Both carried a homozygous FOXI1 variant, c.376T>A (p.Tyr126Asn). Segregation analysis in three unaffected siblings confirmed heterozygous carrier status or homozygous wild-type genotype. Structural modeling demonstrated distinct pathogenic mechanisms among reported FOXI1 variants. Variants affecting Leu146 and Arg213 primarily disrupted protein–DNA interactions without substantial structural destabilization. In contrast, Y126N significantly destabilized the FOXI1 protein (ΔΔG −1.687 ± 0.254 kcal/mol, p = 0.0220), likely impairing function indirectly.

Conclusion

We report two additional individuals with syndromic dRTA caused by a homozygous FOXI1 variant, expanding the limited number of genetically confirmed cases. Structural modeling indicates variant-specific pathogenic mechanisms, with Y126N primarily impairing protein stability. These findings broaden the clinical and molecular spectrum of FOXI1-associated disease and support inclusion of FOXI1 in genetic testing for hereditary dRTA, particularly in patients with hearing impairment.

Funding

• Private Foundation Support