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  • Test code: 72037
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    Saliva and assisted saliva are accepted; DNA is not accepted
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  1. Test Catalog
  2. Invitae Nephrolithiasis Panel

Invitae Nephrolithiasis Panel

Test description

The Invitae Nephrolithiasis Panel analyzes 35 genes that are associated with nephrolithiasis/kidney stone disease.

These genes were selected based on the available evidence to date to provide a broad panel for disorders involving nephrolithiasis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations.

This panel has assay limitations that are different from most of our other diagnostic panels. Please see the Assay section below for more details.

Genes tested

ADCY10 AGXT ALPL APRT ATP6V0A4 ATP6V1B1 CA2 CASR CLCN5 CLDN16 CLDN19 CYP24A1 FAM20A GPHN GRHPR HOGA1 HPRT1 KCNJ1 MOCOS MOCS1 OCRL PREPL SLC12A1 SLC22A12 SLC26A1 SLC2A9 SLC34A1 SLC34A3 SLC3A1 SLC4A1 SLC7A9 SLC9A3R1 UMOD VDR XDH

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Primary panel (35 genes)

ADCY10 AGXT ALPL APRT ATP6V0A4 ATP6V1B1 CA2 CASR CLCN5 CLDN16 CLDN19 CYP24A1 FAM20A GPHN GRHPR HOGA1 HPRT1 KCNJ1 MOCOS MOCS1 OCRL PREPL SLC12A1 SLC22A12 SLC26A1 SLC2A9 SLC34A1 SLC34A3 SLC3A1 SLC4A1 SLC7A9 SLC9A3R1 UMOD VDR XDH

Clinical information

Gene Condition
ADCY10 Absorptive hypercalciuria
AGXT Primary hyperoxaluria type 1
ALPL Hypophosphatasia
APRT Adenine phosphoribosyltransferase deficiency
ATP6V0A4 Renal tubular acidosis, with deafness
ATP6V1B1 Renal tubular acidosis, with deafness
CA2 Osteopetrosis, with renal tubular acidosis
CASR Familial hypocalciuric hypercalcemia (FHH), Autosomal dominant hypocalcemia (ADH), Neonatal hyperparathyroidism
CLCN5 Dent disease complex
CLDN16 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis, type 1
CYP24A1 Hypercalcemia, infantile 1
FAM20A Amelogenesis imperfecta
GPHN Molybdenum cofactor deficiency
GRHPR Primary hyperoxaluria type 2
HOGA1 Primary hyperoxaluria type 3
HPRT1 Lesch-Nyhan syndrome
KCNJ1 Bartter syndrome, type 2, antenatal
MOCOS Xanthinuria, type II
MOCS1 Molybdenum cofactor deficiency A
OCRL Lowe syndrome, Dent disease 2
PREPL Congenital myasthenic syndrome 22, hypotonia-cystinuria syndrome
SLC2A9 Hypouricemia, renal, 2
SLC3A1 Cystinuria
SLC4A1 Distal renal tubular acidosis (dRTA), dRTA with haemolytic anemia, Southeast Asian ovalocytosis (SAO), hereditary spherocytosis
SLC7A9 Cystinuria
SLC9A3R1 Nephrolithiasis/osteopetrosis, hypophosphatemic 1, 2
SLC2A9 Hypouricemia, renal, 2
SLC12A1 Bartter syndrome
SLC22A12 Hypouricemia, renal 1
SLC26A1 Nephrolithiasis, calcium oxalate
SLC34A1 Nephrolithiasis/osteopetrosis, hypophosphatemic,1
SLC34A3 Hypophosphatemic rickets with hypercalciuria
UMOD Hyperuricemic nephropathy, familial juvenile 1
VDR Vitamin D-dependent rickets, type IIA
XDH Xanthinuria type I

Nephrolithiasis or kidney stone formation affects between 5-10% of the population. There are both genetic and environmental causes. Kidney stones are associated with pain, surgical intervention and can lead to chronic kidney disease (CKD) and end stage renal disease (ESRD) (PMID: 26787776, 29240373). Most kidney stones are calcium-containing (PMID:27932479). Other kidney stones contain uric acid, cystine and magnesium ammonium phosphate. Metabolic factors such as hypercalciuria, hyperoxaluria and hypocitraturia may help determine the underlying cause of the nephrolithiasis (PMID: 27932479). If these factors are absent from a 24 hour urine, identifying a systemic cause for the nephrolithiasis is less likely (PMID: 27456839). Familial hypercalciuric nephrolithiasis is responsible for over 35% of patients (PMID: 18486720). Monogenic causes account for over 15% of cases and in 40% of one cohort, identifying the underlying genetic cause led to specific management and treatment options (PMID: 25296721, 26787776).

% Disorder attributed to pathogenic variants in specific genes
Disorder % of Pathogenic variants in genes
Dent disease CLCN5 60%
OCRL1 15-20%
Primary hyperoxaluria AGXT 80%
GRHPR 9%
HOGA1 11%
Cystinuria SLC3A1 and SLC7A9 85% (PMID: 22480232)
Lesch-Nyhan disease HPRT1 90-95% (PMID: 11018746)
Lowe syndrome OCRL 80-90% (PMID:27011217)

Genes on the Nephrolithiasis panel can be inherited in an autosomal dominant, autosomal recessive or X-linked fashion. Several genes on the Nephrolithiasis panel can be inherited in either autosomal dominant or autosomal recessive fashion. Recessive genes are more likely to be the cause for affected infants and children and autosomal dominant inheritance for adult onset forms (PMID: 25296721, 26787776).

Gene Condition Autosomal recessive Autosomal dominant X-linked recessive
ADCY10 Absorptive hypercalciuria X
AGXT Primary hyperoxaluria type 1 X
ALPL Hypophosphatasia X X
APRT Adenine phosphoribosyltransferase deficiency X
ATP6V0A4 Renal tubular acidosis, with deafness X
ATP6V1B1 Renal tubular acidosis, with deafness X
CA2 Osteopetrosis, with renal tubular acidosis X
CASR Familial hypocalciuric hypercalcemia (FHH), Autosomal dominant hypocalcemia (ADH), Neonatal hyperparathyroidism X X
CLCN5 Dent disease complex X
CLDN16 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis, type 1 X
CYP24A1 Hypercalcemia, infantile 1 X
FAM20A Amelogenesis imperfecta X
GPHN Molybdenum cofactor deficiency X X
GRHPR Primary hyperoxaluria type 2 X
HOGA1 Primary hyperoxaluria type 3 X
HPRT1 Lesch-Nyhan syndrome X
KCNJ1 Bartter syndrome, type 2, antenatal X
MOCOS Xanthinuria, type II X
MOCS1 Molybdenum cofactor deficiency A X
OCRL Lowe syndrome, Dent disease 2 X
PREPL Congenital myasthenia gravis 22, hypotonia-cystinuria syndrome X
SLC2A9 Hypouricemia, renal, 2 X X
SLC3A1 Cystinuria X
SLC4A1 Distal renal tubular acidosis (dRTA), dRTA with haemolytic anemia, Southeast Asian ovalocytosis (SAO), hereditary spherocytosis X X
SLC7A9 Cystinuria X
SLC9A3R1 Nephrolithiasis/osteopetrosis, hypophosphatemic 1, 2 X
SLC12A1 Bartter syndrome X
SLC22A12 Hypouricemia, renal 1 X
SLC26A1 Nephrolithiasis, calcium oxalate X
SLC34A1 Nephrolithiasis/osteopetrosis, hypophosphatemic, 1 X
SLC34A3 Hypophosphatemic rickets with hypercalciuria X
UMOD Hyperuricemic nephropathy, familial juvenile 1 X
VDR Vitamin D-dependent rickets, type IIA X X
XDH Xanthinuria type I X

Kidney stones affect approximately 7-13% of the population in North America, 5-9% in Europe and 1-5% in Asia (PMID: 28213860). Cystinuria is the most common cause of monogenic nephrolithiasis (PMID: 29061541) affecting 1 in 7,000 worldwide, ranging from 1 in 2500 Libyan Jews to 1 in 15,000 in the US (PMID: 23334384).

This test may be appropriate for patients with:

  • Stones or nephrocalcinosis in infancy and childhood
  • Failure to thrive and ESRD in infancy or early childhood
  • Recurrent calcium oxalate stones or nephrocalcinosis in adults
  • Family history of primary hyperoxaluria
  • High levels of oxalate in urine or plasma

  1. Braun, DA, et al. Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis. Clin J Am Soc Nephrol. 2016; 11(4):664-72. PMID: 26787776
  2. Moayyeri, A, et al. Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome-Wide Mendelian Randomization Study. J. Bone Miner. Res. 2018; 33(4):643-650. PMID: 29232479
  3. Gambaro, G, et al. Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. J. Nephrol. 2016; 29(6):715-734. PMID: 27456839
  4. Worcester, EM, Coe, FL. Nephrolithiasis. Prim. Care. 2008; 35(2):369-91, vii. PMID: 18486720
  5. Halbritter, J, et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J. Am. Soc. Nephrol. 2015; 26(3):543-51. PMID: 25296721
  6. Sorokin, I, et al. Epidemiology of stone disease across the world. World J Urol. 2017; 35(9):1301-1320. PMID: 28213860
  7. Edvardsson, VO, et al. Hereditary causes of kidney stones and chronic kidney disease. Pediatr. Nephrol. 2013; 28(10):1923-42. PMID: 23334384
  8. Eggermann, T, et al. Cystinuria: an inborn cause of urolithiasis. Orphanet J Rare Dis. 2012; 7:19. PMID: 22480232
  9. Jinnah, HA, et al. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat. Res. 2000; 463(3):309-26. PMID: 11018746
  10. Bökenkamp, A, Ludwig, M. The oculocerebrorenal syndrome of Lowe: an update. Pediatr. Nephrol. 2016; 31(12):2201-2212. PMID: 27011217
  11. Policastro, LJ, et al. Personalized Intervention in Monogenic Stone Formers. J. Urol. 2018; 199(3):623-632. PMID: 29061541

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Based on review of current medical guidelines and peer-reviewed publications, our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. Any variants that fall outside these regions are not analyzed unless otherwise noted. Any specific limitations in the analysis of these genes are also listed in the table below.

We use our Boosted Exome assay to analyze the genes included in this panel. To ensure high sensitivity and specificity of calls, the exome is sequenced to an average depth of 150x, with all positions covered to a minimum depth of 20x unless otherwise noted. Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants and insertions and deletions <15bp in length. Sensitivity to detect insertions and deletions larger than 15bp but smaller than a full exon may be marginally reduced. This assay is not intended to detect indels >50 bp. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. The Invitae Boosted Exome includes detection of multi-exon-level copy number variants for clinically-relevant genes, although the resolution for detectable CNV lengths varies among genes due to sequence and coverage properties, and can also be influenced by DNA quality. The assay is not intended to detect variants in mitochondrial DNA. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ADCY10 NM_018417.5
AGXT NM_000030.2
ALPL* NM_000478.5
APRT NM_000485.2
ATP6V0A4* NM_020632.2
ATP6V1B1 NM_001692.3
CA2 NM_000067.2
CASR NM_000388.3
CLCN5 NM_000084.4
CLDN16 NM_006580.3
CLDN19 NM_148960.2
CYP24A1 NM_000782.4
FAM20A NM_017565.3
GPHN NM_020806.4
GRHPR NM_012203.1
HOGA1 NM_138413.3
HPRT1 NM_000194.2
KCNJ1* NM_000220.4
MOCOS NM_017947.2
MOCS1 NM_001075098.3
OCRL NM_000276.3
PREPL NM_006036.4
SLC12A1 NM_000338.2
SLC22A12 NM_144585.3
SLC26A1* NM_213613.3
SLC2A9 NM_020041.2
SLC34A1 NM_003052.4
SLC34A3 NM_080877.2
SLC3A1 NM_000341.3
SLC4A1 NM_000342.3
SLC7A9* NM_014270.4
SLC9A3R1 NM_004252.4
UMOD NM_003361.3
VDR NM_001017535.1
XDH NM_000379.3

ALPL: Deletion/duplication analysis is not offered for exon 2.
ATP6V0A4: Deletion/duplication and sequencing analysis is not offered for exon 12.
KCNJ1: Deletion/duplication analysis is not offered for this gene.
SLC26A1: Deletion/duplication analysis is not offered for this gene.
SLC7A9: Deletion/duplication analysis is not offered for exon 13.

References

  1. Braun, DA, et al. Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis. Clin J Am Soc Nephrol. 2016; 11(4):664-72. PMID: 26787776
  2. Bökenkamp, A, Ludwig, M. The oculocerebrorenal syndrome of Lowe: an update. Pediatr. Nephrol. 2016; 31(12):2201-2212. PMID: 27011217
  3. Edvardsson, VO, et al. Hereditary causes of kidney stones and chronic kidney disease. Pediatr. Nephrol. 2013; 28(10):1923-42. PMID: 23334384
  4. Eggermann, T, et al. Cystinuria: an inborn cause of urolithiasis. Orphanet J Rare Dis. 2012; 7:19. PMID: 22480232
  5. Gambaro, G, et al. Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement. J. Nephrol. 2016; 29(6):715-734. PMID: 27456839
  6. Halbritter, J, et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J. Am. Soc. Nephrol. 2015; 26(3):543-51. PMID: 25296721
  7. Jinnah, HA, et al. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat. Res. 2000; 463(3):309-26. PMID: 11018746
  8. Moayyeri, A, et al. Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome-Wide Mendelian Randomization Study. J. Bone Miner. Res. 2018; 33(4):643-650. PMID: 29232479
  9. Policastro, LJ, et al. Personalized Intervention in Monogenic Stone Formers. J. Urol. 2018; 199(3):623-632. PMID: 29061541
  10. Sorokin, I, et al. Epidemiology of stone disease across the world. World J Urol. 2017; 35(9):1301-1320. PMID: 28213860
  11. Worcester, EM, Coe, FL. Nephrolithiasis. Prim. Care. 2008; 35(2):369-91, vii. PMID: 18486720

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