Distal Renal Tubular Acidosis Panel

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.

SLC4A1-associated dRTA can be inherited in an autosomal dominant or recessive manner. The autosomal dominant form (childhood onset) is more common and is rarely associated with blood cell abnormalities (featured by hemolytic anemia) while the recessive type (onset earlier than the dominant form) is less common and is usually (but not always) concurrent with hemolytic anemia, mostly seen in Southeast Asia.

Patients with CA2 deficiency present recessive combined proximal and distal (mixed) RTA. Proximal RTA (pRTA) is characterized by reduced proximal nephron bicarbonate reabsorption. In addition to mixed pRTA and dRTA, these patients can have intracerebral calcifications, cognitive impairment, osteopetrosis, and hearing loss. However, phenotypes vary greatly and genotype-phenotype correlations have not been established.

Recessive ATP6V1B1 pathogenic variants cause dRTA with congenital or early onset sensorineural deafness (Karet et al. 1999; Stover et al. 2002). The majority of this type of dRTA are diagnosed by age 1. Hearing loss is mostly diagnosed by age 3.

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 in early childhood. 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).

The basolateral anion exchanger 1 (AE1) encoded by the SLC4A1 gene (19 coding exons) has the greatest expression abundance in erythrocytes and type A acid-secreting intercalated cells of the renal collecting duct. Therefore, a wide spectrum of SLC4A1 pathogenic variants has been associated with dRTA and/or blood cell abnormalities (Alper 2009; Alper 2010; Batlle et al. 2012). Trafficking defects in the mutant AE1 protein is the underlining mechanism for dRTA while blood cell abnormalities are due to a dosage effect (unstable mRNA). Genetic defects of SLC4A1 found to date include missense, nonsense, splicing, regulatory mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving SLC4A1 have not been reported to date. SLC4A1 pathogenic variants associated with isolated dRTA are clustered throughout the transmembrane domains and the short C-terminal cytoplasmic tail. SLC4A1-associated dRTA can be inherited in an autosomal dominant or recessive manner.

CA2 deficiency is an autosomal recessive disorder caused by CA2 pathogenic variants (Venta et al. 1991; Hu et al. 1992). CA2 has 7 exons that encode the cytosolic carbonic anhydrase II, which catalyzes reversible hydration of carbon dioxide. Genetic defects of CA2 found to date include missense, nonsense, splicing mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving CA2 have not been reported.

Distal renal tubular acidosis (dRTA) with sensorineural deafness is an autosomal recessive disorder caused by ATP6V1B1 pathogenic variants (Karet et al. 1999; Stover et al. 2002). ATP6V1B1 has 14 coding exons that encode the B1-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 ATP6V1B1 found to date include missense, nonsense, splicing mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving ATP6V1B1 have not been reported.

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). ATP6V0A4 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.

Detection rate of pathogenic variants in SLC4A1 and CA2 in a large cohort of patients with distal renal tubular acidosis (dRTA) is unknown in the literature because only a limited number of cases have been reported.

In the original study that identified ATP6V1B1 pathogenic variants in autosomal recessive dRTA, Karet et al. studied 31 unrelated kindred (27 had family history of consanguineous marriage) and found ATP6V1B1 pathogenic variants in 19 (61%) cases (Karet et al. 1999). In another study of 26 patients with autosomal recessive dRTA, of which 23 were consanguineous, ATP6V1B1 pathogenic variants were found in 10 (38%) cases (Stover et al. 2002).

In the original study that identified ATP6V0A4 pathogenic variants in autosomal recessive dRTA with normal hearing, Karet et al. studied 13 unrelated kindred (12 had family history of consanguineous marriage) and found ATP6V0A4 mutations 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).

Exon-level large deletions involving ATP6V0A4 have been reported (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).