Nephronophthisis-Like Nephropathy-1 (NPHPL1) via the XPNPEP3 Gene

Nephronophthisis (NPH) is the most common genetic cause of progressive renal failure in children and young adults. NPH is characterized by polyuria, growth retardation, and progressive deterioration of renal function with normal or slightly reduced kidney size (Hildebrandt et al. Nat Genet 17:149-153, 1997; Hildebrandt et al. J Am Soc Nephrol 20:23-35, 2009). Nephronophthisis-like nephropathy-1 (NPHPL1) patients develop a renal disease reminiscent of nephronophthisis within the first three decades of life (O’Toole et al. J Clin Invest 120:791-802, 2010). Renal biopsies from NPHPL1 patients showed characteristic features of nephronophthisis, such as thickening, splitting, and attenuation of the tubular basement membrane, atrophic tubules, and mild interstitial fibrosis, while renal ultrasound revealed increased echogenicity and cysts (O’Toole et al. 2010). Extrarenal features of NPHPL1 include hypertension, essential tremor, high frequency sensorineural hearing loss, and arachnoid cysts on brain imaging. In addition, severe cases of NPHPL1 might develop a mitochondrial disorder with isolated complex I deficiency activity in muscle, seizures, mental retardation, hypertrophic dilated cardiomyopathy, and chronic pancreatitis with pancreatic cysts or hepatic involvement (O’Toole et al. 2010).

NPHPL1 is inherited in an autosomal recessive manner. Variants in the XPNPEP3 gene cause NPHPL1 (O’Toole et al. J Clin Invest 120:791-802, 2010). XPNPEP3 gene encodes a mitochondrial protein known as X-prolyl aminopeptidase 3 (XPNPEP3), which belongs to a family of X-prolyl aminopeptidases that utilize a metal cofactor and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position (Ersahin et al. Arch Biochem Biophys 435:303-310, 2005). XPNPEP3 localizes to the mitochondria of the renal cells, yet it is predicted to have a cilia-related function. Biochemical studies demonstrated that several ciliary proteins are likely XPNPEP3 substrates (Ersahin et al. 2005; O’Toole et al. 2010). A frameshift variant and a splicing variant within the XPNPEP3 gene have been reported (O’Toole et al. 2010).

Sensitivity of this test is currently unknown.

This test provides full coverage of all coding exons of the XPNPEP3 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).