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

AbstractCongenital 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 containingCOL4A1 (13q33 –34) has been implicated in vesicoureteral reflux (VUR), but mutations inCOL4A1 have not been reported in CAKUT. We hypothesized thatCOL4A1 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 inCOL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations inCOL4A1 in 11 individuals from 11 unrelated families with CAKUT, while noCOL4A1 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 theCOL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). WhereasCOL4A1-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 subst...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research