Abstract: PO1671
Additional Mutations in NRIP1 in Families with Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT)
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
- Zheng, Bixia, Boston Children's Hospital, Boston, Massachusetts, United States
- Schneider, Sophia, Boston Children's Hospital, Boston, Massachusetts, United States
- Deutsch, Konstantin, Boston Children's Hospital, Boston, Massachusetts, United States
- Wang, Chunyan, Boston Children's Hospital, Boston, Massachusetts, United States
- Seltzsam, Steve, Boston Children's Hospital, Boston, Massachusetts, United States
- Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States
- Wu, Chen-Han Wilfred, 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
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. In a previous study, we identified a dominant mutation in nuclear receptor interacting protein 1 (NRIP1) as causing urinary tract malformations via dysregulation of retinoic acid signaling (JASN 28:2364, 2017), which remains the only family with NRIP1 mutation reported so far.
Methods
To identify additional families with NRIP1 mutations, we performed whole exome sequencing (WES) in 232 families with CAKUT. We also screened for mutations in NRIP1 in a cohort of 59 affected individuals with small kidneys and a suspected diagnosis of nephronophthisis (NPHP).
Results
By WES analyses, we discovered three heterozygous mutations (one frameshift and two missense) in three unrelated CAKUT families. In particular, individual B3864 with bilateral hydroureteronephrosis and right grade 5 vesicoureteral reflux (VUR) carried a heterozygous frameshift variant (c.2028_2031del; p.Asn676Lysfs*27). Individual A3460 with left renal agenesis harbored a heterozygous missense variant (c.970C>T; p.His324Tyr). In individual A782 with right renal agenesis, we identified a heterozygous missense variant (c.1343G>A; p.Arg448Gln). Family B3977 with an NPHP diagnosis, showing bilaterally increased echogenicity and corticomedullary cysts, carried a heterozygous missense variant (c.2252T>G; p.Leu751Arg). The four variants occurred 2, 0, 2, and 17 times, respectively as heterozygous in the gnomAD database of 125,000 healthy control individuals. All affected individuals exhibited an isolated CAKUT phenotype.
Conclusion
This study confirms that germline mutations in the transcription co-factor NRIP1 gene are a novel genetic cause of human autosomal dominant CAKUT and strengthens the association between retinoic acid and renal malformations.