Autosomal Recessive Renal Tubular Dysgenesis (RTD) via the ACE Gene

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset of persistent anuria (leading to oligohydramnios) and the absence or incomplete differentiation of proximal tubules (Gribouval et al. 2005; Gribouval et al. 2012). Affected individuals may die in utero or within 24 hours of birth. The histopathological hallmark of the disease is absence or paucity of differentiated proximal tubules, which may be associated with skull ossification defects. Renal lesions and early anuria result from renin-angiotensin system inactivity caused by defects in the genes encoding renin (REN), angiotensinogen (AGT), angiotensin converting enzyme (ACE) or angiotensin II receptor type 1 (AGTR1).

Autosomal recessive renal tubular dysgenesis is a consequence of renin-angiotensin system inactivity caused by defects in the genes encoding renin (REN), angiotensinogen (AGT), angiotensin converting enzyme (ACE) or angiotensin II receptor type 1 (AGTR1) (Gribouval et al. 2005; Gribouval et al. 2012). These genes play a crucial role in the reninangiotensin system during human kidney development.

Genetic defects of ACE found in renal tubular dysgenesis include missense, nonsense, splicing mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving ACE have been reported, but are uncommon. The ACE gene encodes the angiotensin I converting enzyme, which is an important regulator of blood pressure and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II, which is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance.

In the most comprehensive study by far of 48 autosomal recessive RTD families (Gribouval et al. 2012), mutations were found in one of the REN, AGT, ACE and AGTR1 genes for all cases fulfilling the clinical, pathological, and immunohistochemical criteria for RTD. Mutations in the ACE gene were found in 31 families (64.6%). Since exon-level copy number changes were found to be very rare in the ACE gene, the mutation detection rate via Sanger sequencing is expected to be around 64.6% for cases fulfilling the clinical, pathological, and immunohistochemical criteria for RTD.

This test provides full coverage of all coding exons of the ACE gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).