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Missense Variants in GFRA1 and NPNT Are Associated with Congenital Anomalies of the Kidney and Urinary Tract

Lookup NU author(s): Professor John SayerORCiD, Dr Noel Edwards



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 by the authors.The use of next-generation sequencing (NGS) has helped in identifying many genes that cause congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT, and its association with autosomal recessively inherited genes is expanding. Highly consanguineous populations can impact the detection of recessively inherited genes. Here, we report two families harboring homozygous missense variants in recently described genes, NPNT and GFRA1. Two consanguineous families with neonatal death due to CAKUT were investigated. Fetal ultrasound of probands identified BRA in the first family and severe renal cystic dysplasia in the second family. Exome sequencing coupled with homozygosity mapping was performed, and Sanger sequencing was used to confirm segregation of alleles in both families. In the first family with BRA, we identified a homozygous missense variant in GFRA1: c.362A>G; p.(Tyr121Cys), which is predicted to damage the protein structure. In the second family with renal cystic dysplasia, we identified a homozygous missense variant in NPNT: c.56C>G; p.(Ala19Gly), which is predicted to disrupt the signal peptide site. We report two Saudi Arabian consanguineous families with CAKUT phenotypes that included renal agenesis caused by missense variants in GFRA1 and NPNT, confirming the role of these two genes in human kidney development.

Publication metadata

Author(s): Al-Hamed MH, Sayer JA, Alsahan N, Edwards N, Ali W, Tulbah M, Imtiaz F

Publication type: Article

Publication status: Published

Journal: Genes

Year: 2022

Volume: 13

Issue: 10

Online publication date: 21/09/2022

Acceptance date: 12/09/2022

Date deposited: 07/11/2022

ISSN (electronic): 2073-4425

Publisher: MDPI


DOI: 10.3390/genes13101687

PubMed id: 36292572


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