Hypophosphatemic Nephrolithiasis/Osteoporosis-2 (NPHLOP2) via the NHERF1/SLC9A3R1 Gene

Nephrolithiasis is a clinical condition in which urinary supersaturation leads to stone formation in the urinary system (the lumen of the collecting system, ureter, and bladder) (Braun et al. 2016; Halbritter et al. 2015; Gee et al. 2016). Patients with kidney stones may have no symptoms or may present with flank pain, gross or microscopic hematuria, obstruction of one or both kidneys, and urinary infections. It affects 10%-15% of adults in their lifetime. SLC9A3R1-associated nephrolithiasis presents with hypophosphatemia and decreased renal phosphate resorption characterized by significantly decreased tubular maximum for phosphate resorption per glomerular filtration rate (TmP/GFR) (Karim et al. 2008). Some patients may also have a spinal deformity and decreased bone mineral density (BMD).

SLC9A3R1-associated nephrolithiasis is an autosomal dominant disorder (Karim et al. 2008; Halbritter et al. 2015). The NHERF1/SLC9A3R1 gene (six coding exons) encodes sodium-hydrogen exchanger regulatory factor 1 (NHERF1), which controls renal phosphate transport. To date, documented genetic defects of NHERF1 include both missense and truncating variants (Human Gene Mutation Database). Large deletions/duplications have not been reported to date.

In the original report of SLC9A3R1-associated nephrolithiasis, 4 of 92 (4.3%) unrelated patients with either nephrolithiasis or bone demineralization were found to have a heterozygous pathogenic NHERF1 variant (Karim et al. 2008).

In an international cohort comprising 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16), Halbritter et al. detected likely (or suspected) causative variants in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases (Halbritter et al. 2015). Two families (0.75%) were found to have a heterozygous pathogenic NHERF1 variant.

In another international pediatric cohort comprising 143 individuals under 18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20), Braun et al. detected likely (or suspected) causative variants in 14 of the same set of 30 genes known nephrolithiasis/nephrocalcinosis genes, leading to a molecular diagnosis in 16.8% (24 of 143) (Braun et al. 2016). One individual (0.7%) was found to have a heterozygous pathogenic NHERF1 variant.

This test provides full coverage of all coding exons of the NHERF1 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).