Kidney Week

Abstract: PO1347

Excess Burden of Rare Coding Variants in Mutation Intolerant Genes in Patients with Kidney Malformations

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Milo Rasouly, Hila, Columbia University Irving Medical Center, New York, New York, United States

Hila Milo Rasouly, PhD

• Krishna Murthy, Sarath Babu, Columbia University Irving Medical Center, New York, New York, United States

Sarath Babu Krishna Murthy,

• Povysil, Gundula, Columbia University Irving Medical Center, New York, New York, United States

Gundula Povysil,

• Marasa, Maddalena, Columbia University Irving Medical Center, New York, New York, United States

Maddalena Marasa,

• Martino, Jeremiah, Columbia University Irving Medical Center, New York, New York, United States

Jeremiah Martino,

• Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)

Velibor Tasic,

• Fiaccadori, Enrico, Universita degli Studi di Parma Dipartimento di Medicina e Chirurgia, Parma, Emilia-Romagna, Italy

Enrico Fiaccadori,

• Ghiggeri, Gian Marco, Istituto Giannina Gaslini, Genova, Liguria, Italy

Gian Marco Ghiggeri,

• Masnata, Giuseppe, Azienda Ospedaliera Brotzu, Cagliari, Sardegna, Italy

Giuseppe Masnata,

• Sanna-Cherchi, Simone, Columbia University Irving Medical Center, New York, New York, United States

Simone Sanna-Cherchi,

• Kiryluk, Krzysztof, Columbia University Irving Medical Center, New York, New York, United States

Krzysztof Kiryluk,

• Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States

Ali G. Gharavi,

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. The contribution of rare variants has not been systematically examined.

Methods

To evaluate the contribution of rare variants to RHD, we analyzed exome sequencing (ES) data in 1,265 unrelated RHD cases and 13,303 unrelated controls. We used gene-level burden analysis, comparing the proportion of cases and controls carrying rare variants per gene across 20 statistical models.

Results

We observed a 1.63-fold case enrichment for rare variants (p= 1.5x10^-6) in known genes associated with dominant forms of kidney diseases (165 cases versus 1,075 controls in 172 known genes), including PAX2 (7.6x10^-8) and HNF1B (5.6x10^-6). All other known genes did not reach statistical significance (p-value>10^-3). Applying a similar approach, we observed a 1.35-fold case enrichment for rare missense variants (p= 5.8x10^-6) in genes constrained against missenses (misZ >3.09) and a 1.59-fold enrichment for rare protein truncating variants (PTV; p= 2.4x10^-9) in genes constrained against PTV (pLI>0.9 and oe lof upper<0.35). We particularly identified a 2.38-fold enrichment for PTV in 421 genes constrained against PTV, expressed in the mouse developing kidney (E15.5), and not known to be associated with human kidney disease (p=1.4x10^-6, Fig.). After curating publicly available databases, we identified at least 23 novel candidate genes, which will require validation in additional human cohorts or analysis of animal models.

Conclusion

We detected a significant excess of rare variants in mutation intolerant genes that are also expressed during early kidney development, suggesting the existence of many yet-to-be identified causal genes. However, owing to the high genetic heterogeneity of RHD, larger-scale investigations will be required to establish causality for individual genes.

Funding

• NIDDK Support