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Human Genetics

, Volume 138, Issue 3, pp 211–219 | Cite as

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

  • Ali Amar
  • Amar J. Majmundar
  • Ihsan Ullah
  • Ayesha Afzal
  • Daniela A. Braun
  • Shirlee Shril
  • Ankana Daga
  • Tilman Jobst-Schwan
  • Mumtaz Ahmad
  • John A. Sayer
  • Heon Yung Gee
  • Jan Halbritter
  • Thomas Knöpfel
  • Nati Hernando
  • Andreas Werner
  • Carsten Wagner
  • Shagufta Khaliq
  • Friedhelm HildebrandtEmail author
Original Investigation
  • 154 Downloads

Abstract

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.

Notes

Acknowledgements

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.

Author contributions

A.A., A.J.M, I.U., D.B., S.S., A.D., T.J.S., J.A.S., H.Y.G., and J.H. developed and performed gene panel amplification and massive parallel sequencing, performed variant calling, devised and performed the mutational analysis strategy and application, and conducted assessments of genotype-phenotype correlations. A.A., Ay.A., M.A., and S.K recruited patients and gathered detailed clinical information for the study. T.K., N.H., A.W., and C.W. performed functional SLC34A1 studies in cell lines and oocytes. All authors critically reviewed the paper. F.H. conceived of and directed the project. A.A., A.J.M, and F.H. wrote the paper.

Compliance with ethical standards

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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Copyright information

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

Authors and Affiliations

  • Ali Amar
    • 1
    • 2
  • Amar J. Majmundar
    • 1
  • Ihsan Ullah
    • 1
  • Ayesha Afzal
    • 2
  • Daniela A. Braun
    • 1
  • Shirlee Shril
    • 1
  • Ankana Daga
    • 1
  • Tilman Jobst-Schwan
    • 1
  • Mumtaz Ahmad
    • 3
  • John A. Sayer
    • 6
    • 7
    • 8
  • Heon Yung Gee
    • 5
  • Jan Halbritter
    • 4
  • Thomas Knöpfel
    • 9
    • 10
  • Nati Hernando
    • 9
  • Andreas Werner
    • 11
  • Carsten Wagner
    • 9
    • 10
  • Shagufta Khaliq
    • 2
  • Friedhelm Hildebrandt
    • 1
    Email author
  1. 1.Division of Nephrology, Department of Medicine, Harvard Medical SchoolBoston Children’s HospitalBostonUSA
  2. 2.Department of Human Genetics and Molecular BiologyUniversity of Health SciencesLahorePakistan
  3. 3.Ganga Ram Hospital and Fatima Jinnah Medical UniversityLahorePakistan
  4. 4.Division of Nephrology, Department of Internal MedicineUniversity of LeipzigLeipzigGermany
  5. 5.Department of Pharmacology, Brain Korea 21 PLUS Project for Medical SciencesYonsei University College of MedicineSeoulSouth Korea
  6. 6.Institute of Genetic MedicineNewcastle UniversityNewcastleUK
  7. 7.The Newcastle upon Tyne Hospitals NHS Foundation TrustNewcastleUK
  8. 8.NIHR Newcastle Biomedical Research CentreNewcastleUK
  9. 9.Institute of PhysiologyUniversity of ZurichZurichSwitzerland
  10. 10.National Center of Competence in Research NCCR Kidney.CHZurichSwitzerland
  11. 11.Institute for Cell and Molecular Biosciences Newcastle UniversityNewcastle upon TyneUK

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