Proximal Renal Tubular Acidosis with Ocular Abnormalities via the SLC4A4 Gene

Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate reabsorption in the renal proximal tubules. Permanent isolated pRTA usually occurs with ocular abnormalities (Igarashi et al. 1999). Clinical features include severe hyperchloremic acidosis, a decreased tubular capacity for bicarbonate reabsorption (about half normal), growth retardation, mental retardation, nystagmus, cataract, corneal opacities, glaucoma, and defects in the enamel of permanent teeth. Age of onset is typically in childhood or adolescence.

Proximal renal tubular acidosis with ocular abnormalities is an autosomal recessive disorder caused by defects in the SLC4A4 gene (Igarashi et al. 1999; Horita et al. 2005). The SLC4A4 gene (22 coding exons) encodes a sodium bicarbonate cotransporter (NBC) involved in the regulation of bicarbonate secretion and absorption and intracellular pH. To date, documented genetic defects of SLC4A4 include missense, nonsense, and small indels (Human Gene Mutation Database). Large deletions/duplications have not been reported.

Detection rate of pathogenic variants in the SLC4A4 gene in a large cohort of patients with proximal renal tubular acidosis with ocular abnormalities is unknown in the literature because to date only a limited number of cases have been reported. The reported pathogenic variants are all detectable by sequencing.

This test provides full coverage of all coding exons of the SLC4A4 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).