The Phenotypic Spectrum of COL4A3 Heterozygotes

Abstract

Most data on Alport Syndrome (AS) due to COL4A3 are limited to families with autosomal recessive AS or severe manifestations such as focal segmental glomerulosclerosis (FSGS). 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 (0.2%) 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 autosomal dominant AS, we matched COL4A3 heterozygotes 1:5 to non-heterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and end-stage kidney disease (ESKD) (p<0.05 for all comparisons) but not bilateral sensorineural hearing loss (p=0.9). Phenotypic severity tended to be more severe among patients with glycine missense variants located within the collagenous domain. For example, patients with Gly695Arg (n=161) had markedly increased risk of dipstick hematuria (OR 9.47, 95% CI: 6.30, 14.22) and ESKD diagnosis (OR 7.01, 95% CI: 3.48, 14.12) whereas those with PTVs (n=119) had moderately increased risks of dipstick hematuria (OR 1.63, 95% CI: 1.03, 2.58) and ESKD diagnosis (OR 3.43, 95% CI: 1.28, 9.19). Less than a third of patients had albuminuria screening completed, and fewer than 1/3 were taking inhibitors of the renin-angiotensin-aldosterone system (RAASi). Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

Figure 1

Flowchart. This figure does not use USRDS 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 ESKD 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 USRDS data.

Figure 3.

KDIGO CKD Risk Categories for Glycine Collagenous Domain Variants vs. 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 UA 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 ESKD 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 USRDS data.