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Abstract: TH-PO822

Whole-Exome Sequencing Identifies Nephrolithiasis (NL) Candidate Genes in Large Consanguineous Pakistani Families

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Ottlewski, Isabel, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Ullah, Ihsan, University of Health Sciences, Lahore, Pakistan
  • Majmundar, Amar J., Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Amar, Ali, University of Health Sciences, Lahore, Pakistan
  • Khaliq, Shagufta, University of Health Sciences, Lahore, Pakistan
  • Zahoor, Muhammad Yasir, Institute of Biochemistry and Biotechnology, University of Veterinary and Animal sciences, Lahore, Pakistan
  • Shril, Shirlee, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes high patient morbidity, frequent hospitalizations and surgical interventions. We previously detected a monogenic cause in established NL disease genes in 15% of 268 American and European NL families (Halbritter JASN 26:543, 2015) and 7% of 235 Pakistani NL families (Amar Hum Genet 138:211, 2018). We, then, performed whole exome sequencing (WES) in 17 unsolved Pakistani NL families with multiple affected members and prominent consanguinity to discover novel candidate NL genes.

Methods

We performed WES variant analysis by applying multiple recessive and dominant genetic models based on pedigree structure. Candidate disease genes were evaluated further by kidney single-cell mRNA expression (Park Science 360:758, 2018), because known NL genes predominantly exhibit nephron tubular segment expression. Dominant candidate genes were additionally assessed for population variant intolerance, as known dominant NL genes associated with severe phenotypes show high genomic constraint.

Results

We detected deleterious mutations in 24 candidate genes in 12/17 total families.
In 10 families with significant homozygosity (>100 Mb in at least 1 affected family member), we detected deleterious recessive mutations in 10 genes. Of these, we identified 2 novel recessive candidate genes (INPP5B, GGTLC1) based on nephron tubular expression. In 8 families with >3 affected members, we evaluated for dominantly inherited variants and detected deleterious mutations in 14 genes. Of these, we identified 1 dominant candidate gene (HIPK3) based on nephron tubular expression and high population variant intolerance.

Conclusion

By WES of 17 Pakistani NL families, we identified 2 novel recessive and 1 novel dominant candidate NL disease genes.