Distal Renal Tubular Acidosis Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10159 ATP6V0A4 81479,81479 Order Options and Pricing
ATP6V1B1 81479,81479
CA2 81479,81479
SLC4A1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10159Genes x (4)81479 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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.

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for this test are patients with dRTA. This test especially aids in differential diagnosis of similar phenotypes by analyzing multiple genes simultaneously.

Genes

Official Gene Symbol OMIM ID
ATP6V0A4 605239
ATP6V1B1 192132
CA2 611492
SLC4A1 109270
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Alper S.L. 2009. The Journal of Experimental Biology. 212: 1672-83. PubMed ID: 19448077
  • Alper S.L. 2010. Familial renal tubular acidosis. J. Nephrol. 23 Suppl 16: S57–76. PubMed ID: 21170890
  • Batlle D., Haque SK. 2012. Nephrology, Dialysis, Transplantation. 27: 3691-704. PubMed ID: 23114896
  • Hu P.Y. et al. 1997. Human Mutation. 9: 383-7. PubMed ID: 9143915
  • Human Gene Mutation Database (HGMD).
  • Karet F.E. et al. 1999. American Journal of Human Genetics. 65: 1656-65. PubMed ID: 10577919
  • Stover E.H. et al. 2002. Journal of Medical Genetics. 39: 796-803. PubMed ID: 12414817
  • Venta P.J. et al. 1991. American Journal of Human Genetics. 49: 1082-90. PubMed ID: 1928091

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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