Kidney Week

Abstract: FR-PO0137

Phenotypic Expansion of Congenital Anomalies of the Kidney and Urinary Tract Due to TBX18 Variants Includes Genital Anomalies

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 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

• Balbach, Maximilian, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Maximilian Balbach

• Madariaga, Leire, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Leire Madariaga, MD

• Zion, Elena, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Elena Zion, MD

• Fotopoulos, Nellie, Genetics division, Fertilys Inc, Montreal, Quebec, Canada

Nellie Fotopoulos, MSc, PhD

• Marchuk, Daniel, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Daniel Marchuk, MD

• Heilbronner, Sophie, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Sophie Heilbronner

• Riedhammer, Korbinian M., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Korbinian M. Riedhammer, MD

• Prakash, Chiranth M., Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Chiranth M. Prakash, PhD

• Saida, Ken, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Ken Saida, MD, PhD

• Buerger, Florian, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Florian Buerger, MD, PhD

• Hildebrandt, Friedhelm, Division of Nephrology, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

Background

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of chronic kidney disease in children and show marked phenotypic and genetic heterogeneity. Pathogenic variants in the transcription factor TBX18 are an established cause of isolated CAKUT but have not been linked to genital anomalies. We identified a likely causative TBX18 variant in an individual with unilateral renal agenesis and unicornuate uterus. We hypothesized that TBX18 might have a pleiotropic role in genitourinary development and that variants in TBX18 and its interactors may occur in individuals with combined CAKUT and genital phenotypes.

Methods

We performed a systematic literature search to identify known TBX18 interactors, yielding 20 genes that encode proteins with evidence of physical interaction. Interactors were filtered for relevance by including genes with i) reported kidney or genitourinary phenotypes or ii) evidence of kidney expression, based on single-cell mRNA datasets and “The Human Protein Atlas” data, resulting in 17 TBX18 interactors. These genes, alongside TBX18, were screened for variants in our exome data from 1,091 cases with CAKUT.

Results

In total, likely causative variants in TBX18 or its 17 interactors were identified in 25/1,091 cases (2.29%). Of these, 23/25 (92%) were located in established CAKUT genes (TBX18 [n=9], ZMYM2 [n=5], CHD7 [n=5], PBX1 [n=3], SIX1 [n=1]), while 2/25 (8%) were found in candidate genes (PRRX2 [n=1], PBX4 [n=1]). A combined CAKUT and genital phenotype was observed in 6/25 cases (24%), compared to 60/1,066 (5.63%) in the remaining control cohort. Thus, variants in TBX18 or its interactors were significantly enriched in individuals with genital anomalies (OR 5.30, 95%CI 2.11–13.07; Fishers Exact Test, p=0.0028). Two cases with likely causative variants and a genital phenotype were identified in ZMYM2, one case each was observed in TBX18, CHD7, PBX1, and PRRX2, and none in SIX1 and PBX4.

Conclusion

We propose that likely disease-causing variants in TBX18 or four of its interactors may confer a facultative genital phenotype, implicating a potential role of the TBX18 transcriptional interaction network in the development of the kidney and urinary tract as well as in genital development. Notably, we found 23 out of 25 identified variants in previously established CAKUT genes. Further, we propose PRRX2 and PBX4 as two novel candidate genes for CAKUT.