Genotype-First Analysis in an Unselected Health System–Based Population and Phenotypic Severity of COL4A5 Variants

Background: Our knowledge of X-linked Alport Syndrome comes mostly from selected cohorts with more severe disease. Methods: We examined the phenotypic spectrum of X-linked Alport Syndrome in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health records. Patients with COL4A5 variants reported as pathogenic or likely pathogenic in ClinVar, or protein-truncating variants, were each matched with up to 5 controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. Phenotypes examined included dipstick hematuria, bilateral sensorineural hearing loss, proteinuria, decreased estimated glomerular filtration rate, and kidney failure. Results: Out of 170,856 patients, there were 29 hemizygous males (mean age 52 y [SD 20]) and 55 heterozygous females (mean age 59 y [SD 19]) with a pathogenic/likely pathogenic COL4A5 variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any Alport Syndrome phenotypic feature) was highest for non-p.Gly624Asp variants (males: 94%, females: 85%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with kidney failure was highest for males with non-p.Gly624Asp variants (44%), intermediate for males with p.Gly624Asp (15%) and females with non-p.Gly624Asp variants (10%), compared to controls (males: 3%, females 2%). Only 47% of individuals with COL4A5 had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system inhibitors. Only 38% of males and 16% of females had a known diagnosis of Alport Syndrome or thin basement membrane disease. Conclusions: Using a genotype-first approach, we show that men and women with X-linked Alport Syndrome are at higher risk of related phenotypic features with a wider spectrum of severity than has been described previously and variability by genotype.