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Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis

Lookup NU author(s): Professor John SayerORCiD, Dr Andreas Werner


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© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. 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.

Publication metadata

Author(s): 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, Knopfel T, Hernando N, Werner A, Wagner C, Khaliq S, Hildebrandt F

Publication type: Article

Publication status: Published

Journal: Human Genetics

Year: 2019

Volume: 138

Pages: 211-219

Print publication date: 04/03/2019

Online publication date: 18/02/2019

Acceptance date: 07/02/2019

ISSN (print): 0340-6717

ISSN (electronic): 1432-1203

Publisher: Springer Verlag


DOI: 10.1007/s00439-019-01978-x


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