Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33–34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.
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Acknowledgements
We would like to thank the families and study individuals for their contribution. Sequencing and data processing was performed by the Broad and Yale Centers for Mendelian Genomics funded by the National Human Genome Research Institute (UM1 HG008900 to DGM and HLR and U54 HG006504 to RPL). This research was supported by Grants from the National Institutes of Health to F.H. (R01-DK088767). A.M is supported by a Research Training in Pediatric Nephrology Grant (T32-DK007726) and the Harvard Stem Cell Institute Kidney Inter-lab Fellowship Award at Harvard Medical School (F-KP-0003-17-00). C.H.W.W. is supported by funding from the National Institutes of Health T32-GM007748 Grant. D.M.C. is funded by the Health Research Board, Ireland (HPF-206-674), the International Pediatric Research Foundation Early Investigators’ Exchange Program and the Amgen Irish Nephrology Society Specialist Registrar Research Bursary. N.M. is supported by funding from the National Institute of Health (T32-DK007726) Grant at Boston Children’s Hospital. T.M.K. is supported by a Post-Doctoral Fellowship award from the KRESCENT Program, a national kidney research training partnership of the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institutes of Health Research. F.H. and S.S. are supported by the Begg Family Foundation.
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Kitzler, T.M., Schneider, R., Kohl, S. et al. COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans. Hum Genet 138, 1105–1115 (2019). https://doi.org/10.1007/s00439-019-02042-4
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DOI: https://doi.org/10.1007/s00439-019-02042-4