Distal Renal Tubular Acidosis, Autosomal Recessive, via the ATP6V0A4 Gene

Hereditary forms of distal renal tubular acidosis (dRTA) result from impaired acid excretion at intercalated cells in the collecting tubules and are characterized by hyperchloremic metabolic acidosis without bicarbonaturia or diarrhea (Alper 2010; Batlle et al. 2012). Common clinical features include retarded growth, osteomalacia, hypercalciuria, hypocitraturia, nephrocalcinosis, polyuria and hypokalemia. To date, known genetic defects for dRTA have found in genes encoding acid–base transporters including the basolateral anion exchanger 1 (AE1), the cytosolic carbonic anhydrase II (CA2), the B1-subunit (ATP6V1B1) and the A4 unite (ATP6V0A4) of the vacuolar H+-ATPase (V-ATPase). Hearing loss presents in approximately one-third of patients due to defects in subunits of the V-ATPase.

ATP6V0A4 pathogenic variants cause recessive dRTA with normal hearing or late onset hearing loss (Karet et al. 1999; Stover et al. 2002). This type of dRTA presents at early childhood. Of note, hearing loss has been found in the second and third decade of patients’ lives (Stover et al. 2002). Hyperammonemia has been also reported as part of the presentation (Alper 2010).

Distal renal tubular acidosis (dRTA) with normal hearing or late onset hearing loss is an autosomal recessive disorder caused by ATP6V0A4 pathogenic variants (Karet et al. 1999; Stover et al. 2002). The ATP6V0A4 gene has 22 coding exons that encode the A4-subunit of the vacuolar H+-ATPase (V-ATPase), which regulates distal nephron acid secretion and also maintains the proper pH of the fluid in the inner ear.

Genetic defects of ATP6V0A4 found to date include missense, nonsense, splicing mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving ATP6V0A4 have been also reported.

In the original study that identified ATP6V0A4 pathogenic variants in autosomal recessive dRTA with normal hearing, Karet et al. studied 13 unrelated kindreds (12 had family history of consanguineous marriage) and found ATP6V0A4 pathogenic variants in 9 (68%) cases (Karet et al. 1999). In another study of 26 patients with autosomal recessive dRTA, of which 23 were consanguineous, ATP6V0A4 pathogenic variants were found in 12 (46%) cases (Stover et al. 2002).

This test provides full coverage of all coding exons of the ATP6V0A4 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).