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Hum Genet
2019 Mar 01;1383:211-219. doi: 10.1007/s00439-019-01978-x.
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Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis.
Amar A
,
Majmundar AJ
,
Ullah I
,
Afzal A
,
Braun DA
,
Shril S
,
Daga A
,
Jobst-Schwan T
,
Ahmad M
,
Sayer JA
,
Gee HY
,
Halbritter J
,
Knöpfel T
,
Hernando N
,
Werner A
,
Wagner C
,
Khaliq S
,
Hildebrandt F
.
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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.
DK076683 National Institute of Diabetes and Digestive and Kidney Diseases, T32DK007726 National Institute of Diabetes and Digestive and Kidney Diseases (US), Post-doctoral Fellowship Grant Harvard Stem Cell Institute (US), Jared J. Grantham Research Fellowship American Society of Nephrology and Polycystic Kidney Disease Foundation, 2015R1D1A1A01056685 National Research Foundation of Korea, Jo 1324/1-1 Deutsche Forschungsgemeinschaft, HEC1987 Higher Education Commission, Pakistan through National Research Program for Universities, R01 DK076683 NIDDK NIH HHS , R01 DK068306 NIDDK NIH HHS , T32 DK007726 NIDDK NIH HHS , DK076683 NIDDK NIH HHS
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