Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract
Genomics England Research Consortium
(2022) Kidney International, volume 101, issue 5, pp. 1039 - 1053
(Article)
Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and
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cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.
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Keywords: CAKUT, dysplastic kidneys, ROBO1, Slit-Robo signaling, VUR, Nephrology, Journal Article
ISSN: 0085-2538
Publisher: Nature Publishing Group
Note: Funding Information: This work was supported in part by the German Research Foundation ( Deutsche Forschungsgemeinschaft [DFG]— HA 6908/3-1 to JH), the Else Kroener Fresenius Foundation (EKES—to JH), US National Institutes of Health , National Human Genome Research Institute (NHGRI)/ National Heart, Lung, and Blood Institute (NHLBI) UM1 HG006542 to the Baylor Hopkins Center for Mendelian Genomics (JRL) and the National Institute of Neurological Disorders and Stroke ( R35 NS105078 to JRL). JEP was supported by NHGRI K08 HG008986 . BP was supported by the German Research Foundation (DFG) grant PO2366/2-1 . CB receives support from the Deutsche Forschungsgemeinschaft (DFG) (BE 3910/8-1, BE 3910/9-1, and Project-ID 431984000 – Collaborative Research Center SFB 1453) and the Federal Ministry of Education and Research (BMBF, 01GM1903I and 01GM1903G). SD receives a grant for the Initiative on Rare and Undiagnosed Diseases in Pediatrics (no. 18gk0110012h0101 ) from the Japan Agency for Medical Research and Development (AMED) , Tokyo, Japan. LRC was supported by the Dutch Kidney Foundation ( 18OKG19 to AMvE). Several authors of this publication are members of the European Reference Network for Rare Kidney Diseases (ERKNet)—Project ID No. 739532. This research was further made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust , Cancer Research UK , and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The diagnosis of ID 7 was made possible through access to the data generated by the 2025 French Genomic Medicine Initiative. Funding Information: We thank Dr. S. Stoebe (University Medical Center Leipzig) for providing cardiac imaging data. This work was supported in part by the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]—HA 6908/3-1 to JH), the Else Kroener Fresenius Foundation (EKES—to JH), US National Institutes of Health, National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) UM1 HG006542 to the Baylor Hopkins Center for Mendelian Genomics (JRL) and the National Institute of Neurological Disorders and Stroke (R35 NS105078 to JRL). JEP was supported by NHGRI K08 HG008986. BP was supported by the German Research Foundation (DFG) grant PO2366/2-1. CB receives support from the Deutsche Forschungsgemeinschaft (DFG) (BE 3910/8-1, BE 3910/9-1, and Project-ID 431984000 – Collaborative Research Center SFB 1453) and the Federal Ministry of Education and Research (BMBF, 01GM1903I and 01GM1903G). SD receives a grant for the Initiative on Rare and Undiagnosed Diseases in Pediatrics (no. 18gk0110012h0101) from the Japan Agency for Medical Research and Development (AMED), Tokyo, Japan. LRC was supported by the Dutch Kidney Foundation (18OKG19 to AMvE). Several authors of this publication are members of the European Reference Network for Rare Kidney Diseases (ERKNet)—Project ID No. 739532. This research was further made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The diagnosis of ID 7 was made possible through access to the data generated by the 2025 French Genomic Medicine Initiative. JM, JH, and BP conceived the study; JM, ME, JAH, BT, TSh, GA, SD, AP, TWe, AAS, JH, FP, HF, and LD gathered clinical data; LRC and AMvE contributed in identifying further affected individuals; CB, TWa, SD, TSm, DP, TM, ZCA, JEP, SS, SP, JB, JRL, and TA-B performed genetic analysis; BP, RS, and EH performed RNA analysis; BP and AAM performed in silico analysis; GJP, GCG, and CWL contributed murine model analysis; CH and AKH performed antibody validation and immunohistochemistry; AAS, ZCA, JEP, and JRL gave highly appreciated advice for this study and edited the manuscript; JM, ME, BP, JH, and FP wrote the manuscript. All authors read, edited, and accepted the final manuscript version. Publisher Copyright: © 2022 International Society of Nephrology
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