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Hum Genet. 2019 Oct;138(10):1105-1115. doi: 10.1007/s00439-019-02042-4. Epub 2019 Jun 22.

COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.

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Department of Medicine, Boston Children's Hospital, Enders 561, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
Pediatric Nephrology Center of Excellence and Pediatric Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Department of Pediatric Nephrology, Dr. Mehta's Multi-Specialty Hospital, Chennai, India.
Department of Pediatric Nephrology, Institute for Mother and Child Health Care, Belgrade, Serbia.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia.
Department of Medicine, Boston Children's Hospital, Enders 561, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.


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.

[Available on 2020-10-01]
[Indexed for MEDLINE]

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