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Abstract: FR-PO599

Comprehensive Genetic Analysis Reveals Novel Variants in Nephrolithiasis and Nephrocalcinosis

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Saida, Ken, Boston Children's Hospital, Boston, Massachusetts, United States
  • Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
  • Ottlewski, Isabel, Boston Children's Hospital, Boston, Massachusetts, United States
  • Salmanullah, Daanya, Boston Children's Hospital, Boston, Massachusetts, United States
  • Yu, Seyoung, Boston Children's Hospital, Boston, Massachusetts, United States
  • Kolvenbach, Caroline Maria, Boston Children's Hospital, Boston, Massachusetts, United States
  • Lemberg, Katharina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Mansour, Bshara, Boston Children's Hospital, Boston, Massachusetts, United States
  • Mertens, Nils David, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hölzel, Selina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Elmubarak, Izzeldin, Boston Children's Hospital, Boston, Massachusetts, United States
  • Franken, Gijs AC, Boston Children's Hospital, Boston, Massachusetts, United States
  • Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Renal stones or nephrolithiasis (NL) and nephrocalcinosis (NC) are clinically heterogeneous conditions. The etiology of renal stone disease is multifactorial and influenced by a combination of genetic and environmental factors. 33 monogenic causes of NL/NC have been identified to date; we have shown that a genetic cause of NL/NC can be identified in approximately 11 % of adults and 16-20% of children (Halbritter JASN 26:543, 2015; Braun CJASN 11: 664, 2016). Several investigations have been conducted using next-generation sequencing (predominantly targeted sequencing). Nonetheless, a comprehensive genetic analysis of NL/NC, particularly in terms of copy number variation (CNV), is yet to be done.

Methods

Individuals with a history of at least one renal stone or NC before the age of 25 years were recruited from international stone clinics between January 2013 and December 2020. Affected individuals with NL/NC from 285 families were enrolled in this study. Exome sequencing (ES) was performed to determine the genetic cause of NL/NC. Detected variants were assessed using a population database, evolutionary conservation, and in silico pathogenicity prediction scores, and categorized according to the American College of Medical Genetics (ACMG) guidelines. Furthermore, CNVs were analyzed using sequencing coverage data.

Results

37 Likely disease-causing variants were detected in 42 families, leading to genetic diagnosis in 14.7% (42/285) of all cases. Of the 37 detected variants, 20 were novel. The CTNS gene was the most frequent (n=8), followed by AGXT (n=5), SLC3A1 (n=4), ATP6V1B1 (n=3), and ATP6V0A4 (n=2). The other genes included CLCN5, CLDN16, CLDN19, MOCOS, SLC4A1, SLC7A9, SLC12A1, SLC34A1, and BSND. CNVs were detected in three cases. Homozygous deletions in SLC3A1 were detected in two cases: one showed deletion in exon 4-9, and the other showed a deletion involving only exon 7.

Conclusion

Our data represent a comprehensive analysis of the monogenic causes of renal stone disease. In-depth analysis at the single-exon level is beneficial. Simultaneous analysis of CNVs and SNVs based on ES has potential as a first-choice diagnostic approach for renal stone disease.