#3166 recognition of renal tubular dysgenesis in adolescent ckd by biallelic agt variants required broad genetic analysis

Abstract Background and Aims Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare inherited disorder of renal (tubular) development, clinically characterized by fetal oligo-/anuria leading to oligohydramnion and Potter sequence, resulting in high mortality within the prenatal and neonatal period. Variants in genes encoding components of the renin-angiotensin system (RAS) are causative for this disorder. Herein, we report 2 European families with biallelic variants within AGT and aim to provide novel insides into disease understanding. Method The study was approved by our institutional ethics committee (approval number: 251_18 B). Clinical, histological and pedigree analysis were performed. Exome sequencing of a preselected gene panel (nephroma, 560 genes associated with renal disease) was analysed on the HiSeq System 2500 (Illumina) after enrichment by TWIST human core technology (TWIST Bioscience). Immunohistochemistry staining (IHC) and in-situ hybridization (ISH) for expression of renin were performed on kidney biopsy. In addition, renin expression was determined in primary tubular cells of the index patient by qPCR. Allele frequencies of heterozygous and biallelic predicted deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. Results The first family was identified after transition from pediatric to adult nephrology at the University Hospital Erlangen. Initially, the male index patient of consanguineous Turkish descent presented with oligohydramnion in the prenatal period. Directly after birth (32nd gestational week) he suffered from profound hypotension, pulmonary hypoplasia and pulmonary stenosis, as well as third degree acute kidney injury leading to ICU treatment, but no need of hemodialysis. He survived the perinatal period while a decline in renal function was observed over time leading to CKD G3b at the age of 19 years. Exome sequencing revealed a previously reported pathogenic homozygous missense variant within AGT (c.1224G>A, p.Arg375Gln). Kidney biopsy at the age of 14 years revealed tubulointerstitial fibrosis, profound glomerulocystic changes with partly glomerulosclerosis and vasculopathic features. IHC and ISH showed recruitment and strong expression of renin in tubular cells and vessels, where cultured primary tubular cells also showed strong expression of renin. Circulating renin was profoundly elevated, with normal levels of aldosterone. The patient is not hypertensive and receives no antihypertensive medications. The family history revealed at least 2 miscarriages due to oligohydramnion. The second family was identified from the Genomics England 100,000 Genomes Project. The male index patient presented with prenatal bilateral hydronephrosis. He was delivered prematurely around the 35th gestational week. Both kidneys suffered from chronic bilateral urinary reflux leading to CKD G2 at the age of 8 years. Family history revealed one prior miscarriage. Genetic analysis revealed two compound heterozygous missense variants within AGT (c.842A>G, p.Tyr281Cys; c.151T>C, p.Cys51Arg). The heterozygous allele frequency in the Genomics England cohort for AGT predicted deleterious variants was very low. Therefore, we would predict a biallelic hit with the respective disease as an ultra-rare event. Reviewing the literature, to our knowledge 18 individuals are reported to date with different biallelic variants within AGT. From these cases only three survived the perinatal period. It is not reported if these individuals reached adulthood. Conclusion We hereby demonstrate two extremely rare cases, affected by biallelic variants within AGT, that survived the perinatal period and eventually led to chronic kidney disease. Since the phenotypes may be variable, a contemporary approach by broad genetic analysis is the only option to decode the genetic background in individuals with a suspected genetic disorder. Upregulation of renin in tubular cells by inactivation of AGT in the germline may drive tubulointerstitial fibrosis, which is a theoretical concern regarding ongoing targeted pharmacological approaches against AGT for arterial hypertension.