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Beyond the kidney: extra-renal manifestations of monogenic nephrolithiasis and their significance

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Abstract

Background

The objective of this study was to explore the frequency of occurrence of extra-renal manifestations associated with monogenic nephrolithiasis.

Methods

A literature review was conducted to identify genes that are monogenic causes of nephrolithiasis. The Online Mendelian Inheritance in Man (OMIM) database was used to identify associated diseases and their properties. Disease phenotypes were ascertained using OMIM clinical synopses and sorted into 24 different phenotype categories as classified in OMIM. Disease phenotypes caused by the same gene were merged into a phenotypic profile of a gene (PPG) such that one PPG encompasses all related disease phenotypes for a specific gene. The total number of PPGs involving each phenotype category was measured, and the median phenotype category was determined. Phenotype categories were classified as overrepresented or underrepresented if the number of PPGs involving them was higher or lower than the median, respectively. Chi-square test was conducted to determine whether the number of PPGs affecting a given category significantly deviated from the median.

Results

Fifty-five genes were identified as monogenic causes of nephrolithiasis. A total of six significantly overrepresented and three significantly underrepresented phenotype categories were identified (p < 0.05). Four phenotypic categories (growth, neurological, skeletal, and abdomen/gastrointestinal) are significantly overrepresented after Bonferroni correction for multiple comparisons (p < 0.002). Among all phenotypes, impaired growth is the most common manifestation.

Conclusion

Recognizing the extra-renal manifestations associated with monogenic causes of kidney stones is critical for earlier diagnosis and optimal care in patients.

Graphical abstract

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Data availability

The datasets analyzed during the current study is available at OMIM (https://www.omim.org/search/advanced/clinicalSynopsis) and the Human Protein Atlas database (https://www.proteinatlas.org/).

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Authors and Affiliations

  1. Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, 11100 Euclid Ave., Cleveland, OH, 44106, USA

    Chen-Han Wilfred Wu, Jad Badreddine, Ethan Su, Kimberly Tay, Hsin-Ti Cindy Lin, Stephen Rhodes & Donald Bodner

  2. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, 11100 Euclid Ave., Cleveland, OH, 44106, USA

    Chen-Han Wilfred Wu, Jad Badreddine, Ethan Su & Hsin-Ti Cindy Lin

  3. Department of Population and Quantitative Health Sciences, School of Medicine, Cleveland, OH, USA

    Fredrick Schumacher

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All listed authors contributed to this manuscript through data collection, analysis, interpretation, writing, and reviewing the manuscript.

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Correspondence to Chen-Han Wilfred Wu.

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Donald Bodner owns stock shares in Fortec Litho Inc. The other authors report no conflict of interest.

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Wu, CH.W., Badreddine, J., Su, E. et al. Beyond the kidney: extra-renal manifestations of monogenic nephrolithiasis and their significance. Pediatr Nephrol 39, 1429–1434 (2024). https://doi.org/10.1007/s00467-023-06242-z

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