Kidney Week

Abstract: FR-PO0126

Variant Type Determines the Degree of Retinal Structural Disruption in Alport Syndrome: A TTIMax Atlas Across 37 Unique COL4A3-A5 Variants

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

• Mekki, Ossama, University of Utah Health, Salt Lake City, Utah, United States

Ossama Mekki, MD

• Ibrahim, Abdelrahman, Hennepin Healthcare System Inc, Minneapolis, Minnesota, United States

Abdelrahman Ibrahim, MD, MBChB

• Awadallah, Mina, University of Utah Health, Salt Lake City, Utah, United States

Mina Awadallah, MD

• Sameh, Ahmed, University of Utah Health, Salt Lake City, Utah, United States

Ahmed Sameh, MD, MBChB

• Abuelsamen, Tamer, University of Utah Health, Salt Lake City, Utah, United States

Tamer Abuelsamen, MD

• Khalil, Menatallah Y., Alexandria University, Alexandria, Alexandria Governorate, Egypt

Menatallah Y. Khalil, MD, MBChB

• Hinckley, Mckinnon, University of Utah Health, Salt Lake City, Utah, United States

Mckinnon Hinckley

• Al-Rabadi, Laith, University of Utah Health, Salt Lake City, Utah, United States

Laith Al-Rabadi, MD

Background

Temporal retinal thinning on optical coherence tomography is a well-recognized feature of Alport syndrome, yet the relative TTIMax burden associated with individual COL4A3, COL4A4, and COL4A5 variants remains incompletely characterized. We constructed a mutation-specific TTIMax atlas to systematically rank these variants by degree of temporal retinal thinning.

Methods

We evaluated TTIMax derived from optical coherence tomography (OCT) in 89 genetically confirmed Alport syndrome patients. Using a compiled mutation-level dataset, we built a variant-level atlas that preserved per-mutation TTIMax values. For each variant, we calculated n, mean, median, standard deviation, range, and coefficient of variation. Variants were ranked by mean TTIMax, and recurrent variants (n ≥ 2) were analyzed separately to provide more stable estimates.

Results

The atlas encompassed 37 unique variants across 89 TTIMax observations. The highest mean TTIMax among all variants was observed for the singleton COL4A5 frameshift c.3326_3327insT (p.Gly1110Argfs*27) at 19.35%. Among recurrent variants, COL4A5 p.Gly576Ser showed the highest mean TTIMax at 14.09% (n = 3), followed by COL4A3 c.2313_2330del at 13.19% (n = 2). At the opposite extreme, the lowest overall mean was seen with COL4A5 p.Gly406Asp at 6.28% (n=1), while the lowest recurrent mean was observed for COL4A3 p.Arg1661Cys at 6.81% (n = 4). The most frequently observed variants — COL4A5 p.Leu1655Arg (n = 15, mean 9.46%), COL4A5 p.Cys1570Ser(n = 16, mean 8.71%), COL4A3 p.Gly695Arg (n = 12, mean 7.12%), and COL4A4 c.559-2A>C (n = 4, mean 8.25%) — clustered near the previously established high-burden threshold of 8.01%, with 26 of 37 variants exceeding this threshold.

Conclusion

TTIMax enables construction of a mutation-specific atlas that ranks COL4 variants by temporal retinal thinning burden. This approach may provide a useful framework for variant-level phenotypic stratification and may help refine genotype-phenotype interpretation in Alport syndrome.