Abstract: SA-PO810
Exome Sequencing in Individuals with CAKUT Identifies De Novo Variants in Novel Candidate Genes in 15.5%
Session Information
- Genetic Diseases: Glomerulopathies - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Kolvenbach, Caroline Maria, Boston Children's Hospital, Boston, Massachusetts, United States
- Merz, Lea Maria, Boston Children's Hospital, Boston, Massachusetts, United States
- Wang, Chunyan, Boston Children's Hospital, Boston, Massachusetts, United States
- Mertens, Nils David, Boston Children's Hospital, Boston, Massachusetts, United States
- Seltzsam, Steve, Boston Children's Hospital, Boston, Massachusetts, United States
- Mansour, Bshara, Boston Children's Hospital, Boston, Massachusetts, United States
- Hölzel, Selina, Boston Children's Hospital, Boston, Massachusetts, United States
- Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
- Lemberg, Katharina, Boston Children's Hospital, Boston, Massachusetts, United States
- Saida, Ken, Boston Children's Hospital, Boston, Massachusetts, United States
- Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
- Nicolas Frank, Camille H., Boston Children's Hospital, Boston, Massachusetts, United States
- Yousef, Kirollos, 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
- Hilger, Alina, University of Erlangen, Erlangen, Germany
- Tasic, Velibor, Medical Faculty of Skopje, Skopje, Macedonia (the former Yugoslav Republic of)
- Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background
Congenital anomalies of the kidney and urinary tract (CAKUT) represents the most frequent birth defect and encompasses a large variety of malformations arising from defective nephrogenesis. To date, mutations in 50 monogenic genes are known to cause CAKUT. However, in only 15-20% of CAKUT cases a causative mutation in a known monogenic CAKUT gene can be identified. Recent studies show the impact of de novo variants in FOXP1 and ZMYM2 in individuals with CAKUT, suggesting that de novo variants contribute to the genetic disease etiology.
Methods
In this study, we performed exome sequencing (ES) in 731 families out of which 264 were trio families in order to detect novel CAKUT candidate genes.
Results
i) Through proband-parent based evaluation, a variant in a single candidate gene was detected in 79 of 264 families (29.9%). ii) In 41 of 264 trio families (15.5%), we identified strong de novo variants in 43 potential novel CAKUT candidate genes. a) Of these 43 de novo variants, truncating or splice site de novo variants were found in nine genes (ASPHD1, COPS7A, DUSP23, FBXW7, GRHL1, MTHFD1, PLA2G4A, SLTM, SOX13). b) Four de novo variants were detected in murine CAKUT genes (AGRN, COPS7A, PDE1A, PDS5A). c) Interestingly, a relatively high percentage of de novo variants (25.6%, 11 out of 43) occurred in genes that are involved in transcription (BRPF1, BSX, COPS7A, DLX3, FBXW7, GRHL1, IRX6, PROX1, SLTM, SOX13, TLK2). d) Four de novo variants were found in genes that are paralogs of known disease causing CAKUT genes (AGRN, HSP90AB1, PTPRZ1, SOX13). Scoring variants in identified genes based on these categories (a-d), identified COPS7A and SOX13 as the most promising new candidate genes for CAKUT.
Conclusion
Our findings suggest that de novo variants in novel candidate genes may contribute to the CAKUT pathogenesis. Here, we propose two novel candidate genes for CAKUT.