Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity of COL4A5 variants.

Autor:	Zellers M; Geisinger Commonwealth School of Medicine, Scranton, PA., Solanki K; Department of Population Health Sciences, Geisinger, Danville, PA., Kelly MA; Department of Genomic Health, Geisinger, Danville, PA., Murphy KM; Geisinger, Danville, PA., Retterer K; Geisinger, Danville, PA., Kirchner HL; Department of Population Health Sciences, Geisinger, Danville, PA., Bucaloiu ID; Department of Nephrology, Geisinger, Danville, PA., Moore B; Department of Genomic Health, Geisinger, Danville, PA., Mirshahi T; Department of Genomic Health, Geisinger, Danville, PA., Chang AR; Department of Population Health Sciences, Geisinger, Danville, PA.; Department of Nephrology, Geisinger, Danville, PA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 09. Date of Electronic Publication: 2024 Aug 09.
DOI:	10.1101/2024.06.04.24308453
Abstrakt:	Introduction: Our knowledge of X-linked Alport Syndrome [AS] comes mostly from selected cohorts with more severe disease. Methods: We examined the phenotypic spectrum of X-linked AS 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 (P) or likely pathogenic (LP) in ClinVar, or protein-truncating variants (PTVs), were each matched with up to 5 controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. AS-related phenotypes included dipstick hematuria, bilateral sensorineural hearing loss (BSHL), proteinuria, decreased eGFR, and ESKD. Results: Out of 170,856 patients, there were 29 hemizygous males (mean age 52.0 y [SD 20.0]) and 55 heterozygous females (mean age 59.3 y [SD 18.8]) with a COL4A5 P/LP variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any AS phenotypic feature) was highest for non-p.Gly624Asp P/LP variants (males: 94%, females: 85%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with ESKD was highest for males with P/LP variants (44%), intermediate for males with p.Gly624Asp (15%) and females with P/LP 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 (RAAS) inhibitors. Only 38% of males and 16% of females had a known diagnosis of Alport syndrome or thin basement membrane disease. Conclusion: In an unselected cohort, we show increased risks of AS-related phenotypes in men and women compared to matched controls, while showing a wider spectrum of severity than has been described previously and variability by genotype. Future studies are needed to determine whether early genetic diagnosis can improve outcomes in Alport Syndrome. Competing Interests: Conflicts of interest: No potential conflicts of interest relevant to this article were reported.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu