Journal
HUMAN GENETICS
Volume 138, Issue 3, Pages 211-219Publisher
SPRINGER
DOI: 10.1007/s00439-019-01978-x
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Funding
- National Institutes of Health [5R01DK068306-14]
- NIH Training Grant in Pediatric Nephrology [T32DK007726]
- Harvard Stem Cell Institute Kidney Group
- 2018 Polycystic Kidney Disease Foundation Jared J. Grantham Research Fellowship
- National Research Foundation of Korea [2018R1A5A2025079]
- Deutsche Forschungsgemeinschaft [Jo 1324/1-1]
- Higher Education Commission, Pakistan through National Research Program for Universities grant [HEC1987]
- Higher Education Commission, Pakistan
- Kidney Research UK
- Northern Counties Kidney Research Fund
- National Center of Competence in Research NCCR Kidney
- Swiss National Science Foundation
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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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