Kidney Week

Abstract: FR-PO0144

Expanding the Phenotypic Presentation of Novel TBC1D8B Variants in Adults with Kidney Disease

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

• Saepian, Duangporn, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand

Duangporn Saepian, MD

• Thotsiri, Sansanee, Mahidol University Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand

Sansanee Thotsiri, MD

• Kitiyakara, Chagriya, Mahidol University Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand

Chagriya Kitiyakara, MD

• Wongboonsin, Janewit, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand

Janewit Wongboonsin, MD, MS

Introduction

TBC1D8B is an X-linked gene essential for podocyte structural integrity. It was curated at moderate evidence for nephrotic syndrome (NS) type 20 by ClinGen with the mechanism of disease being loss-of-function. The phenotype of kidney disease were mostly young onset NS up to 19 years old; however, its full spectrum of kidney disease presentation could still be expanded. We report 3 cases with unique presentations: two cases of adult-onset ESKD without a prior history of NS, and one case of steroid resistant NS (SRNS) with a dramatic response to rituximab.

Case Description

Patients 1 and 2 presented at age 25 with asymptomatic severe hypertension and advanced CKD. Despite no previous history of proteinuric disease, both progressed rapidly to ESKD within two years. Whole-genome sequencing (WGS) identified a hemizygous 2-bp deletion (c.1289_1290del; p.Val430Glufs*3) in Patient 1 and a nonsense variant (c.2064T>A; p.Tyr688Ter) in Patient 2.
Patient 3 presented at age 12 with SRNS and biopsy-confirmed FSGS. Although he carried the same variant as Patient 1, he achieved a dramatic and sustained clinical remission for over two years following rituximab therapy, which was administered prior to the genetic results. In all three cases, the variants were inherited from asymptomatic carrier mothers with normal renal function.

Discussion

This series expands the TBC1D8B spectrum to include a "silent" CKD phenotype bypassing classic Nephrotic Syndrome (NS). The dramatic response to rituximab observed in Patient 3 challenges the view that genetic podocytopathies are uniformly refractory to immunotherapy. The c.1289_1290del variant in two unrelated families suggests an East Asian founder effect. The presence of other very small number of hemizygotes in gnomad suggest the unique nature of this loss-of-function variant in this gene, rather than benignity. Future research should explore the mechanistic pathways and genotype-phenotype correlations beyond traditional NS

Clinical and genetic description of case series