Abstract: PO1630
Generation of Monogenic Candidate Genes of Human Nephrotic Syndrome via Three Independent Approaches
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Onuchic-Whitford, Ana C., Boston Children's Hospital, Boston, Massachusetts, United States
- Klambt, Verena, Boston Children's Hospital, Boston, Massachusetts, United States
- Mao, Youying, Boston Children's Hospital, Boston, Massachusetts, United States
- Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
- Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
- Shamseldin, Hanan Elfadil, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Deutsch, Konstantin, Boston Children's Hospital, Boston, Massachusetts, United States
- Kitzler, Thomas Michael, Boston Children's Hospital, Boston, Massachusetts, United States
- Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States
- Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
- Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
- Rehm, Heidi L., Broad Institute, Cambridge, Massachusetts, United States
- Mane, Shrikant M., Yale University School of Medicine, New Haven, Connecticut, United States
- Alkuraya, Fowzan S., King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background
Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease in childhood. The finding of >60 single-gene causes of SRNS, mainly through whole-exome sequencing (WES), has contributed to the understanding of its disease mechanisms. Whereas in ~12-30% of cases with onset <25yo, a monogenic cause is detected, most cases remain molecularly unsolved. This indicates that additional monogenic causes of SRNS may exist.
Methods
We generated 3 independent lists of candidate genes: 1) 63 published monogenic mouse models of nephrotic syndrome (NS) or proteinuria, obtained from stringent review of published databases and literature; 2) 64 genes, whose podocytic expression is regulated by WT1 (Lefebvre Kidney Int 88:321, 2015); and 3) a discovery set of 120 candidate genes that we generated by WES analysis of 1,382 NS families over 12 years. We first validated candidate lists 1) and 2) for overlap with 63 known human SRNS genes. We then overlapped candidate lists 1) (mouse models) and 2) (WT1-regulated genes) with our 120 WES-derived candidate genes (3), in order to identify potential novel genes that may cause monogenic NS.
Results
Twelve of the 63 NS mouse models (1) and 5 of the 64 WT1-regulated genes (2) overlapped with the control set of 63 known human SRNS genes, indicating relevance of the 2 candidate gene lists. When we evaluated for overlap with our 120 WES-derived candidate genes, 6 overlapped with the mouse candidate list (1), and 4 with the WT1-regulated candidate list (2). Of note, 3 genes (SYNPO, SEMA3G, ITGB8) were shared by all 3 lists. We found a homozygous SYNPO mutation (c.2540C>T, p.P847L) in a 4yo patient with NS. We show that loss-of-function of SYNPO decreases CDC42 activity and reduces podocyte migration rate, both rescued by overexpression of wild type cDNA, but not by cDNA representing the patient mutation.
Conclusion
By overlapping 2 candidate gene sets with a set of 120 genes resulting from WES analysis in 1,382 families with NS, we identified SYNPO as a potential novel monogenic cause of NS.
Funding
- NIDDK Support