Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity of COL4A5 variants.
medRxiv
; 2024 Aug 09.
Article
en En
| MEDLINE
| ID: mdl-38883771
ABSTRACT
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
MedRxiv
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Estados Unidos