Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant patient morbidity. We previously demonstrated a genetic cause of NL can be identified in 11–29% of pre-dominantly American and European stone formers. Pakistan, which resides within the Afro-Asian stone belt, has a high prevalence of nephrolithiasis (12%) as well as high rate of consanguinity (> 50%). We recruited 235 Pakistani subjects hospitalized for nephrolithiasis from five tertiary hospitals in the Punjab province of Pakistan. Subjects were surveyed for age of onset, NL recurrence, and family history. We conducted high-throughput exon sequencing of 30 NL disease genes and variant analysis to identify monogenic causative mutations in each subject. We detected likely causative mutations in 4 of 30 disease genes, yielding a likely molecular diagnosis in 7% (17 of 235) of NL families. Only 1 of 17 causative mutations was identified in an autosomal recessive disease gene. 10 of the 12 detected mutations were novel mutations (83%). SLC34A1 was most frequently mutated (12 of 17 solved families). We observed a higher frequency of causative mutations in subjects with a positive NL family history (13/109, 12%) versus those with a negative family history (4/120, 3%). Five missense SLC34A1 variants identified through genetic analysis demonstrated defective phosphate transport. We examined the monogenic causes of NL in a novel geographic cohort and most frequently identified dominant mutations in the sodium–phosphate transporter SLC34A1 with functional validation.
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F.H. is the William E. Harmon Professor of Pediatrics. This research is supported by a grant from the National Institutes of Health to F.H. (5R01DK068306-14). A.M. is supported by a NIH Training Grant in Pediatric Nephrology (T32DK007726), by the 2017 Post-doctoral Fellowship Grant from the Harvard Stem Cell Institute Kidney Group, and by the 2018 Polycystic Kidney Disease Foundation Jared J. Grantham Research Fellowship. H.Y.G is supported by the National Research Foundation of Korea (2018R1A5A2025079). T.J.S. is supported by the Deutsche Forschungsgemeinschaft (Jo 1324/1-1). S.K. is supported by Higher Education Commission, Pakistan through National Research Program for Universities grant (HEC1987). A.A. is supported by International Research Support Initiative Program grant for doctoral studies by Higher Education Commission, Pakistan. J.A.S. is supported by Kidney Research UK and the Northern Counties Kidney Research Fund. C.A.W. is supported by the National Center of Competence in Research NCCR Kidney. CH financed by the Swiss National Science Foundation.
Conflict of interest
F.H. is a co-founder of Goldfinch Biopharma Inc. The other authors declare that they have no competing financial interests. No part of this manuscript has been previously published.
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Amar, A., Majmundar, A.J., Ullah, I. et al. Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis. Hum Genet 138, 211–219 (2019). https://doi.org/10.1007/s00439-019-01978-x