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Abstract: TH-PO701

Analysis of De-Novo Coding Mutations Identifies New Candidate Genes for Kidney Malformations

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Milo Rasouly, Hila, Columbia University, New York, New York, United States
  • Marasa, Maddalena, Columbia University, New York, New York, United States
  • Kil, Byum hee, Columbia University, New York, New York, United States
  • Lim, Tze Yin, Columbia University, New York, New York, United States
  • Ruan, Thomas L., Columbia University Medical Center, New York, New York, United States
  • Martino, Jeremiah, Columbia University Medical Center, New York, New York, United States
  • Steers, Nicholas J., Columbia University, New York, New York, United States
  • Materna-Kiryluk, Anna, Poznan University of Medical Sciences, Poznan, Poland
  • Masnata, Giuseppe, Azienda Ospedale G. Brotzu, Cagliari, Italy
  • Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
  • Saraga, Marijan, University Hospital in Split, Split, Croatia
  • Ghiggeri, Gian Marco, IRCCS Istituto G. Gaslini , GENOVA, Italy
  • Sampogna, Rosemary V., Columbia University, New York, New York, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
Background

Renal hypodysplasia (RHD) is one of the most common cause of pediatric kidney failure. Although multiple causative genes have been identified, they only account for 10-15% of cases. A search for de-novo “mutations” (DNMs), has led to the identification of numerous novel genes for congenital heart defects and neurodevelopmental disorders. We hypothesized that de-novo analysis can similarly identify new RHD-causing genes.

Methods

Whole-exome sequencing was performed on 88 RHD trios. The sequences were annotated using an in-house software, ATAV, and DNMs were identified. Potential enrichment for DNMs was analyzed with the denovolyzer package in R. Exploratory gene-set enrichment analysis was performed with the Molecular Signatures Database (MSigDB).

Results

We identified a significant 1.5-fold enrichment for DNMs in cases compared to expectations (p= 1.7x10-4). The enrichment mostly originated from probands with renal agenesis or renal hypoplasia, and not from those with multicystic dysplastic kidneys. Globally, the DNM signal was mainly driven by genes that are highly expressed during murine kidney development. De-novo loss-of function mutations were detected only in two genes known to be associated with kidney disorders (PAX2 and TSC2) but none of the missense DNMs occurred in known RHD genes. In pathway analysis, we observed a 11.8-fold enrichment for missenses in genes targeted by NF1 (p= 7.9x10-5), a 4-fold enrichment for DNMs in the CHEK2 network (p= 2.8x10-4) and a 6.4-fold enrichment for DNMs in genes potentially regulated by PAX4 (p= 1.3x10-4). We did not find independent DNMs in the same gene, confirming heterogeneity of disease.

Conclusion

Despite limited sample size, we detected an excess of de-novo mutations in RHD, identifying an important mechanism of disease. Gene-set analysis may help to pinpoint which genes are driving this enrichment. Analysis of larger cohorts is likely to identify genes with recurrent de-novo variants, enabling identification of causal genes.

Funding

  • NIDDK Support