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

Key Points In an unselected health system–based research study, we show that the phenotypic spectrum of X-linked Alport syndrome is wider than previously known. Kidney risks were lower for patients with p.Gly624Asp, a hypomorphic variant that is thought to have originated in Central and Eastern Europe. Many patients in this study had not been diagnosed with Alport syndrome, and consequently, many had not received appropriate testing and treatment. 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 men and women 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 five 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, lower eGFR, and kidney failure. Results Of 170,856 patients, there were 29 hemizygous men (mean age 52 years [SD 20]) and 55 heterozygous women (mean age 59 years [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 the highest for non-p.Gly624Asp variants (men: 94%, women: 85%) and intermediate for p.Gly624Asp (men: 77%, women: 69%) compared with controls (men: 32%, women: 50%). The proportion with kidney failure was the highest for men with non-p.Gly624Asp variants (44%) and intermediate for men with p.Gly624Asp (15%) and women with non-p.Gly624Asp variants (10%) compared with controls (men: 3%, women: 2%). Only 47% of patients with COL4A5 had completed albuminuria screening, and a minority were taking renin-angiotensin-aldosterone system inhibitors. Only 38% of men and 16% of women 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.