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The Phenotypic Spectrum of COL4A3 Heterozygotes

INTRODUCTION: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied. METHODS: Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we...

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Autores principales: Solanki, Kaushal V., Hu, Yirui, Moore, Bryn S., Abedi, Vida, Avula, Venkatesh, Mirshahi, Tooraj, Strande, Natasha T., Bucaloiu, Ion D., Chang, Alexander R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10577321/
https://www.ncbi.nlm.nih.gov/pubmed/37849993
http://dx.doi.org/10.1016/j.ekir.2023.07.010
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author Solanki, Kaushal V.
Hu, Yirui
Moore, Bryn S.
Abedi, Vida
Avula, Venkatesh
Mirshahi, Tooraj
Strande, Natasha T.
Bucaloiu, Ion D.
Chang, Alexander R.
author_facet Solanki, Kaushal V.
Hu, Yirui
Moore, Bryn S.
Abedi, Vida
Avula, Venkatesh
Mirshahi, Tooraj
Strande, Natasha T.
Bucaloiu, Ion D.
Chang, Alexander R.
author_sort Solanki, Kaushal V.
collection PubMed
description INTRODUCTION: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied. METHODS: 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 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 ADAS, we matched COL4A3 heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. RESULTS: COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure (P < 0.05 for all comparisons) but not bilateral sensorineural hearing loss (P = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg (n = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs (n = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system. CONCLUSION: This study demonstrates a wide spectrum of phenotypic severity in ADAS due to COL4A3 with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.
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spelling pubmed-105773212023-10-17 The Phenotypic Spectrum of COL4A3 Heterozygotes Solanki, Kaushal V. Hu, Yirui Moore, Bryn S. Abedi, Vida Avula, Venkatesh Mirshahi, Tooraj Strande, Natasha T. Bucaloiu, Ion D. Chang, Alexander R. Kidney Int Rep Clinical Research INTRODUCTION: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied. METHODS: 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 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 ADAS, we matched COL4A3 heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. RESULTS: COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure (P < 0.05 for all comparisons) but not bilateral sensorineural hearing loss (P = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg (n = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs (n = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system. CONCLUSION: This study demonstrates a wide spectrum of phenotypic severity in ADAS due to COL4A3 with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS. Elsevier 2023-07-25 /pmc/articles/PMC10577321/ /pubmed/37849993 http://dx.doi.org/10.1016/j.ekir.2023.07.010 Text en © 2023 International Society of Nephrology. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Clinical Research
Solanki, Kaushal V.
Hu, Yirui
Moore, Bryn S.
Abedi, Vida
Avula, Venkatesh
Mirshahi, Tooraj
Strande, Natasha T.
Bucaloiu, Ion D.
Chang, Alexander R.
The Phenotypic Spectrum of COL4A3 Heterozygotes
title The Phenotypic Spectrum of COL4A3 Heterozygotes
title_full The Phenotypic Spectrum of COL4A3 Heterozygotes
title_fullStr The Phenotypic Spectrum of COL4A3 Heterozygotes
title_full_unstemmed The Phenotypic Spectrum of COL4A3 Heterozygotes
title_short The Phenotypic Spectrum of COL4A3 Heterozygotes
title_sort phenotypic spectrum of col4a3 heterozygotes
topic Clinical Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10577321/
https://www.ncbi.nlm.nih.gov/pubmed/37849993
http://dx.doi.org/10.1016/j.ekir.2023.07.010
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