The role of double heterozygotes of SLC3A1 and SLC7A9 in the prevalence of cystine stones.

Autor:	Wilfred Wu CH; Department of Urology and Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH. Electronic address: wilfred.wu@case.edu., Patel I; Department of Urology and Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH., Lovrenert K; Department of Urology and Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH., Eisner B; Massachusetts General Hospital/Harvard Medical School, Boston, MA., Meeks N; Division of Clinical Genetics and Metabolism, Department of Pediatrics, Children's Hospital Colorado and University of Colorado, Aurora, CO., Chun-Hui Tsai A; Section of Genetics, Department of Pediatrics, University of Illinois Chicago, Chicago, IL., Baum M; Division of Nephrology, Boston Children's Hospital/Harvard Medical School, Boston, MA., Berry G; Division of Genetics and Genomics, Boston Children's Hospital/Harvard Medical School, Boston, MA., Schumacher FR; Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Sep 21; Vol. 27 (1), pp. 101281. Date of Electronic Publication: 2024 Sep 21.
DOI:	10.1016/j.gim.2024.101281
Abstrakt:	Purpose: Cystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of SLC3A1 and SLC7A9. Previous publications revealed that clinical prevalence is higher than genetically predicted prevalence. Heterozygotes in either gene are not stone formers. However, double heterozygotes (DH), individuals with 2 heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence. Methods: Because of the rarity of the condition, direct clinical observation is impractical. We perform this population study as a surrogate by identifying the observed DH, deriving the theoretical/expected DH, and testing the null hypothesis (NH) that the observed DH frequency is equal or greater than expected. This NH biologically correlate to that DH are asymptomatic and do not have cystine stone. Results: Using the 1000 Genome Database, we identified 0 DH. We derived the theoretical/expected DH with Hardy-Weinberg Equilibrium and Mendel's law of independent assortment as 4.94 × 10-s. Population proportion test revealed z = -0.353, and P = .362, the NH cannot be rejected. Conclusion: Statistical testing does not support that DH are symptomatic, ie, DH of SLC3A1 and SLC7A9 may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain. Competing Interests: Conflict of Interest Chen-Han Wilfred Wu: Executive Committee of the Harrington Scholar-Innovator Award Program, Clinical Trials with Moderna. Michelle Baum: Clinical Trials with NovoNordisk, scientific advisory with NovoNordisk, ongoing post-marketing study with Alynylam, scientific advisory with Alnylam. Cantero (previously Orfan)-medical advisory; Chinook-medical advisory. (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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