Cystinuria via the SLC7A9 Gene

Cystinuria is characterized by impaired transport of cystine and dibasic amino acids in the proximal renal tubule and gastrointestinal tract (Barbosa et al. 2012). The defective renal reabsorption of cystine leads to the formation of calculi in the urinary tract and consequently, obstructive uropathy, pyelonephritis, and even renal failure. Classification of cystinuria can be based on urine excretion of cystine and dibasic amino acids or genetic profiling (Font-Llitjós et al. 2005; Dello Strologo et al. 2002).

The inheritance of cystinuria is not clear cut (Dello Strologo et al. 2002). In general, cystinuria shows classic autosomal recessive inheritance. However, obligate heterozygote carriers have variable urinary excretion of cystine and dibasic amino acids and may develop nephrolithiasis. Therefore, cystinuria sometimes can be regarded as an autosomal dominant disorder with incomplete penetrance (Barbosa et al. 2012). SLC3A1 and SLC7A9 are the two known cystinuria causative genes.

The SLC7A9 gene (12 coding exons) encodes a member protein of light subunits of amino acid transporters, which functions in the reabsorption of cystine in the kidney tubule. To date, documented genetic defects of SLC7A9 include missense, nonsense, splicing variants, small indels and large deletions/duplications (Human Gene Mutation Database). In particular, large deletions and duplications are common in both SLC3A1 and SLC7A9 (Schmidt et al. 2003; Barbosa et al. 2012).

86.8% of mutant alleles were identified in a mutation screen for SLC3A1 and SLC7A9 in 164 probands from the International Cystinuria Consortium (Font-Llitjós et al. 2005). Of the fully explained probands, 56 (34.1%) and 68 (41.5%) have two pathogenic variants found in SLC3A1 and SLC7A9, respectively.

Large deletions and duplications are common in both SLC3A1 and SLC7A9 (Schmidt et al. 2003; Barbosa et al. 2012). Large rearrangements were found in 33.3% of mutant alleles (5 in SLC3A1 and 1 in SLC7A9) in a cohort of 12 Portuguese patients affected with cystinuria (Barbosa et al. 2012). In another cohort of 49 patients, 7 and 3 showed copy number variants in SLC3A1 and SLC7A9, respectively (Schmidt et al. 2003).

This test provides full coverage of all coding exons of the SLC7A9 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).