The Phenotypic Spectrum of COL4A3 Heterozygotes

Abstract

Introduction: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied.

Methods: Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined ADAS, we matched COL4A3 heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis.

Results: COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure (P < 0.05 for all comparisons) but not bilateral sensorineural hearing loss (P = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg (n = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs (n = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system.

Conclusion: This study demonstrates a wide spectrum of phenotypic severity in ADAS due to COL4A3 with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

Keywords: Alport Syndrome; Chronic Kidney Disease; Clinical Epidemiology; Genetic Renal Disease; Kidney Failure.

Graphical abstract

Figure 1

Flowchart. This figure does not use United States Renal Data System data.

Figure 2

KDIGO CKD risk categories by variant groups. KDIGO CKD Risk Categories: Hematuria only category had trace hematuria but eGFR >60 and ACR <30; moderately increased risk (eGFR >60 with ACR 30–300 or eGFR 45–59 with ACR <30); high risk (eGFR >60 with ACR >300, eGFR 45–59 with ACR 30–300, eGFR 30–44 with ACR <30); very high risk (eGFR 15–29 with ACR <30, eGFR 15–44 with ACR 30–300, eGFR 30–59 with ACR >300), extremely high risk (eGFR <15 or eGFR 15–29 with ACR >300, or kidney failure by ICD code). If ACR data was unavailable, urinalysis data was used with dipstick 1+ twice classified as ACR 30–299 mg/g and dipstick 2+ twice or greater classified as ACR 300+ mg/g. This figure does not include any United States Renal Data System data. ACR, urine albumin-to-creatinine ratio; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ICD, International Classification of Diseases; KDIGO, Kidney Disease Improving Global Outcomes.

Figure 3

KDIGO CKD Risk Categories for Glycine Collagenous Domain Variants versus Controls, by Age Group. This figure includes 169 patients heterozygous for glycine variants in the collagenous domain (including 129 Gly695Arg), and 1475 controls with eGFR and urinalysis data. KDIGO CKD Risk Categories: Hematuria only category had trace hematuria but eGFR >60 and ACR <30; moderately increased risk (eGFR >60 with ACR 30–300 or eGFR 45–59 with ACR <30); high risk (eGFR >60 with ACR >300, eGFR 45–59 with ACR 30–300, eGFR 30–44 with ACR <30); very high risk (eGFR 15–29 with ACR <30, eGFR 15–44 with ACR 30–300, eGFR 30–59 with ACR >300), extremely high risk (eGFR <15 or eGFR 15–29 with ACR >300, or kidney failure by ICD code). If ACR data was unavailable, urinalysis data was used with dipstick 1+ twice classified as ACR 30–299 mg/g and dipstick 2+ twice or greater classified as ACR 300+ mg/g. This figure does not include any United States Renal Data System data. ACR, urine albumin-to-creatinine ratio; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ICD, International Classification of Diseases; KDIGO, Kidney Disease Improving Global Outcomes.