Nephronophthisis: NPHP1 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 years in NPHP1, NPHP2, NPHP3, and NPHP4. 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 1

Clinicalfeatures of familial juvenile nephronophthisis (NPHP1) include anemia,polyuria, polydipsia, isosthenuria, and death in uremia. Hypertension andproteinuria are conspicuous in their absence. Excessive urinary loss of sodiumaccounts for the rarity of hypertension. Symmetrical destruction of the kidneysinvolving both tubules and glomeruli (which were hyalinized) is observed. Theage at death ranges from about 4 to 15 years. This is the second most commoncause of childhood chronic renal failure. 65 to 75% of NPHP1 patients exhibitlarge homozygous deletions in the 2q13 region that includes the NPHP1 gene.

Joubertsyndrome is an autosomal recessive multisystem disease characterized bycerebellar vermis hypoplasia with prominent superior cerebellar peduncles(resulting in the 'molar tooth sign', or MTS, on axial MRI), mentalretardation, hypotonia, irregular breathing pattern, and eye movementabnormalities. Some individuals with JS have retinal dystrophy and/orprogressive renal failure characterized as nephronophthisis. The disorder insuch patients is referred to as cerebellooculorenal syndrome, or CORS.Individuals with a mild form of JS have been shown to have a homozygousdeletion of the NPHP1 gene identical,by mapping, to that in subjects with nephronophthisis alone. Senior-Lokensyndrome, the association of nephronophthisis with autosomal recessiveretinitis pigmentosa, has been observed in patients with homozygous deletion ofthe NPHP1 gene.

For patients with suspected familial juvenile nephronophthisis, deletion/duplication analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by deletion/duplication analysis, sequence 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 familial juvenile nephronophthisis in an individual in whom deletion/duplication analysis was negative
  • Carrier testing in adults with a family history of familial juvenile nephronophthisis in whom deletion/duplication analysis was negative


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

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.
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.
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.
  • Deletion/duplication analysis of the NPHP1 gene by CGH array is available and is recommended before sequence analysis.
  • 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