The population frequency of predicted pathogenic variants in commonly-affected genes in CAKUT in the general population

Background Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of kidney failure in children, and renal imaging suggests that it affects one in 200 of the population, one in five of whom are thought to have a genetic cause. This study determined the population frequency of predicted pathogenic variants from the six most commonly-affected CAKUT genes. Methods HNF1B , SALL1 , EYA1 , PBX1 , GATA3 , PAX2 variants were downloaded from gnomADv.2.1.1 (n = 141,456) and the population frequency of predicted disease-causing variants calculated from the sum of structural, null (loss-of- function) and predicted pathogenic missense changes in the overall cohort and in the ancestries represented. This was compared with the population frequencies derived from ClinVar, HGMD and LOVD. Population frequencies were also determined in a replication cohort (gnomAD v.4.1, n = 807,162) using our method and ClinVar assessments. Results The population frequency of genetic causes of CAKUT lies between one in 249 (our strategy) and one in 1,263 (ClinVar assessments) in the gnomAD v.2.1.1 database. More than half the disease-causing variants were missense changes, and predicted pathogenic variants were commonest in African-Americans (one in 149) and least common in Ashkenazim (one in 864). The population frequency estimated from gnomAD v.4.1 lies between one in 372 (our strategy) and one in 1762 (with ClinVar). Discussion The ClinVar results are underestimates since assessments were not available for structural, copy number and many missense changes in gnomAD. However some of the predicted pathogenic variants identified in this study will have incomplete penetrance or be variably expressive and, therefore, result less often in clinical disease. Nevertheless, these calculations suggest that genetic causes of CAKUT are likely to be more common than the previously-reported one in 1,000.