TY - JOUR
T1 - The Phenotypic Spectrum of COL4A3 Heterozygotes
AU - the Regeneron Genetics Center
AU - Solanki, Kaushal V.
AU - Hu, Yirui
AU - Moore, Bryn S.
AU - Abedi, Vida
AU - Avula, Venkatesh
AU - Mirshahi, Tooraj
AU - Strande, Natasha T.
AU - Bucaloiu, Ion D.
AU - Chang, Alexander R.
N1 - Funding Information:
The authors are grateful to the many patients who contributed to the MyCode Community Health Initiative by providing genomic and electronic health information. The authors thank the Regeneron Genetics Center for providing funding for patient enrollment and exome sequencing for the DiscovEHR study, and the authors would like to acknowledge the Geisinger-Regeneron DiscovEHR Collaboration for the genotypic and phenotypic data. This work was supported by NIGMS grant GM111913 to TM. The authors thank the United States Renal Data System (USRDS) for their support. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government. The data supporting the findings of this study are available within the article and its Supplementary Data files. Additional information for reproducing the results described in the article is available upon reasonable request and subject to a data use agreement. This research was approved by the Geisinger Clinic Institutional Review Board and included participants in the MyCode Health Initiative who have exome sequencing data obtained as part of the Geisinger-Regeneron DiscovEHR collaboration. All participants provided written informed consent, and all experiments were performed in accordance with relevant guidelines and regulations. Study was designed by ARC and NTS; data collection was done by KVS, BSM, TM, VAb, and VAv; analysis was performed by YH and ARC; interpretation of results was conducted by KVS, NTS, IDB, TM, and ARC; manuscript was drafted by KVS and ARC; and the manuscript was revised critically for important intellectual content by all authors. All authors have approved the version to be published.
Funding Information:
The authors are grateful to the many patients who contributed to the MyCode Community Health Initiative by providing genomic and electronic health information. The authors thank the Regeneron Genetics Center for providing funding for patient enrollment and exome sequencing for the DiscovEHR study, and the authors would like to acknowledge the Geisinger-Regeneron DiscovEHR Collaboration for the genotypic and phenotypic data. This work was supported by NIGMS grant GM111913 to TM.
Publisher Copyright:
© 2023 International Society of Nephrology
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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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U2 - 10.1016/j.ekir.2023.07.010
DO - 10.1016/j.ekir.2023.07.010
M3 - Article
AN - SCOPUS:85168508661
SN - 2468-0249
VL - 8
SP - 2088
EP - 2099
JO - Kidney International Reports
JF - Kidney International Reports
IS - 10
ER -
