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Abstract: TH-PO448

Genotype-First Analysis in an Unselected Health System-Based Population Reveals Variable Penetrance of COL4A5 Variants

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic


  • Chang, Alexander R., Geisinger Health, Danville, Pennsylvania, United States
  • Zellers, Mckenzie R., Geisinger Health, Danville, Pennsylvania, United States
  • Solanki, Kaushal V., Geisinger Health, Danville, Pennsylvania, United States
  • Moore, Bryn S., Geisinger Health, Danville, Pennsylvania, United States
  • Mirshahi, Tooraj, Geisinger Health, Danville, Pennsylvania, United States

Current literature suggests that nearly all hemizygous males with COL4A5 mutations (i.e. X-linked Alport Syndrome [AS]) progress to end-stage kidney disease (ESKD) though most data come from selected cohorts.


We used exome sequencing data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health record data to identify patients with COL4A5 variants reported as pathogenic (P) or likely pathogenic (LP) in ClinVar. Phenotypic data sources included the United States Renal Data System (USRDS), ICD codes, blood and urinalysis data. Patients were categorized into Kidney Disease Improving Global Outcomes (KDIGO) risk categories using estimated glomerular filtration rate (eGFR) and albuminuria (preferentially) or urine dipstick protein data.


Out of 174,418 participants, there were 24 hemizygous males (mean age 53.8 [SD 19.5] years) and 55 heterozygous females (mean age 59.8 [SD 17.6]) with a P/LP COL4A5 variant, including Gly624Asp (n=48) and 9 missense and 4 protein truncating variants. Overall, 41% of males had KDIGO severely increased risk category and 4% of females had severely increased risk category with lower severity for Gly624Asp than other variants (Figure). In logistic regression analyses adjusted for age, sex, and race, hemizygous males and heterozygous females were at increased risk of ESKD (females: OR 5.2, 95% CI: 1.2, 21.3; males: OR 36.1, 95% CI: 14.5, 89.7). Few had been diagnosed with Alport Syndrome (21% of males, 9% of females). Only 45% of individuals had completed albuminuria screening, and ~1/3 were taking renin angiotensin aldosterone system (RAAS) inhibitors.


In an unselected cohort, we demonstrate a wider spectrum of kidney severity in men and women than has been described previously with variability by genotype. Future studies are needed to determine whether early genetic diagnosis can improve outcomes in Alport Syndrome.


  • NIDDK Support