Nephronophthisis: INVS Gene Sequencing

Condition Description

Nephronophthisis,an autosomal recessive cystic kidney disease, is the most frequent monogeniccause of renal failure in childhood. There are four forms of nephronophthisiscaused by mutations in four different genes. Clinically, there is astatistically different age at onset at end-stage renal disease: terminal renalfailure develops at median ages of 13 years, 1 year, 19 years, and 11-34 yearsin NPHP1, NPHP2, NPHP3, and NPHP4 respectively. Hallmarks of familialnephronophthisis are tubular basement membrane disruption, interstitiallymphohistiocytic cell infiltration, and development of cysts at thecorticomedullary border of the kidneys. The histology in later stages of NPHalways merges into a chronic sclerosing tubulointerstitial nephropathy, whichis found in chronic renal failure of all origins.

Nephronophthisis 2

Inone study, individuals with infantile nephronophthisis (NPHP2) presented withinthe first months of life with severe renal failure and acidosis, which could beassociated with hypertension and/or polyuria and/or severe cholestatic liverdisease. A renal biopsy, performed in all patients, showed similar featurescharacterized by a diffuse chronic tubulointerstitial nephritis andparticularly by the presence of microcystic dilatation of proximal tubules andBowman space. Progression of the renal disease was extremely rapid and patientscan reach end-stage renal failure before the age of 2 years (11 to 22 months).

Inanother study, phenotypic presentation ranged from a Potter-like syndrome tohyperechogenic kidneys, renal insufficiency, hypertension, and hyperkalemia.Affected individuals showed rapid deterioration of kidney function, leading toend-stage renal failure within 3 years. The manifestations range from prenatalfetal oliguria and oligohydramnios resulting in postnatal respiratory failure anddeath to postnatal onset of disease later than 30 months of age. None of thepostnatally diagnosed patients had a history of either oligohydramnios orneonatal respiratory symptoms. All affected individuals developed anemia,hyperkalemic metabolic acidosis, and increased serum creatine. None of theaffected subjects had polyuria, polydypsia, or associated ocular or hepaticcomplications.

Thespecific clinical features of this disease are its early onset and rapidprogression to end-stage renal failure. Pathologically, it differs fromlater-onset nephronophthisis by the absence of medullary cysts and thickenedtubular basement membranes and by the presence of cortical microcysts. NPHP2 iscaused by mutations in the INVS gene(also known as NPHP2) (9q31). Theprotein product of the INVS gene,inversion, has been shown to interact with that of the NPHP1 gene, nephrocystin.

For patients with suspected infantile nephronophthisis, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

Click here for the OMIM summary on this condition.

Genes (1)

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This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of infantile nephronophthisis
  • Carrier testing in adults with a family history of infantile nephronophthisis


Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient's genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not meant to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient's gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.


Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (
Submit only 1 of the following specimen types
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the INVS genes by CGH array is available for those individuals in whom sequence analysis is negative.
  • Custom diagnostic mutation analysis is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

How to Order

Requisition Forms