Prenatal Diagnosis of Autosomal Recessive Renal Tubular Dysgenesis with Anhydramnios Caused by a Mutation in the AGT Gene

Abstract

Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare and lethal disorder that causes stillbirth or early neonatal death. Most of the reported cases are diagnosed postnatally by a histopathological hallmark of the absence or paucity of differentiated proximal tubules in kidneys. Prenatal diagnosis of ARRTD is challenging because only a few fetal features (e.g., oligohydramnios/anhydramnios, anuria) are associated with this condition. In this study, we report a fetus with ARRTD, which showed anhydramnios and invisible urinary bladder since the second trimester, followed by growth restriction and reversed end diastolic flow in the middle cerebral artery (MCA-REDF). No morphological anomaly was detected on the fetal kidneys during an ultrasound scan. The baby died of refractory hypotension the day after their birth. Genetic analysis of genes that are involved in the renin-angiotensin-aldosterone system (RAAS), which are the known genetic causes of ARRTD, identified a novel, biparental-origin homozygous c.857-619_1269+243delinsTTGCCTTGC mutation in the AGT gene. The mutation is considered as pathogenic because it is cosegregated with ARRTD and detected in other unrelated ARRTD families. Our findings link the fetal ultrasound manifestations to the ARRTD, highlighting clues that are useful for prenatal diagnosis, which warrants confirmatory genotyping of the RAAS genes including oligohydramnios/anhydramnios, anuria (absent filling of a fetal urinary bladder), MCA-REDF, and a morphologically normal kidney.

Whole Exome Sequencing with Comprehensive Gene Set Analysis Identified a Biparental-Origin Homozygous c.509G>A Mutation in PPIB Gene Clustered in Two Taiwanese Families Exhibiting Fetal Skeletal Dysplasia during Prenatal Ultrasound

“…Our results from the in silico prediction and cross-species conservation analysis also demonstrated a strong effect of the c.509G>A mutation in PPIB and cross-species conservation of the p.170 glycine residue, and thus provided additional evidence to support the deleterious nature of the mutation. Since the predominant Han Chinese population of Taiwan is originally from the same region of China, and the two Taiwanese families in our study were unrelated and non-consanguineous, it is plausible that the allele encompassing the mutation of c.509G>A is a result of the founder effect, a phenomenon we had observed in several other monogenic disorders such as aromatic I-amino acid decarboxylase deficiency [33] and AR renal tubular dysgenesis [34]. Among a whole genome sequencing project in the Taiwanese population organized by Taiwan Biobank on more than 1500 healthy individuals, a total of 1514 wild type (c.509G/c.509G) and three heterozygote carriers (c.509G/c.509A) on PPIB c.509 were recorded.…”

Rapid Trio Exome Sequencing for Autosomal Recessive Renal Tubular Dysgenesis in Recurrent Oligohydramnios

“…In addition, the c.857-619_1269 + 243delinsTTGCCTTGC mutation identified in the AGT gene was previously reported in seven Taiwanese families (Ma et al, 2019;Min-Hua et al, 2020). This suggests that this allele may be the result of a founder effect.…”

“…To search for aberrant splicing, we performed in-housedesigned 5-set RT-PCR for RNA from the proband's kidney after termination and revealed two different transcriptions involving exon 2 skipping and exon 3-4 skipping (Figure 3 and Supplementary Figure 1). Further gDNA analysis of another reported deletion (Ma et al, 2019)…”

“… Genomic DNA analysis of the reported deletion in the Taiwanese population using primers as previously reported ( Ma et al, 2019 ). (A) Genomic DNA analysis of family 1.…”

Polymorphism of ACE, AGT, AGTR1 genes as genetic predictors of hypertension

“…Данные полиморфные варианты гена AGT были ассоциированы и сосудистыми осложнениями при беременности и гормонзаместительной терапии (поскольку экспрессия гена AGT повышается в ответ на действие этинил-эстрадиола) [33][34][35][36][37].…”