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Oculocerebrorenal Syndrome of Lowe (Lowe syndrome) and Dent Disease - 2 via the OCRL Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
11539 OCRL 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11539OCRL81479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

The Oculocerebrorenal syndrome of Lowe (OCRL or Lowe syndrome) is a rare X-linked disorder, which is a characterized by a pleiotropic phenotype including congenital bilateral dense cataracts, infantile congenital muscular hypotonia, severe intellectual disability and Fanconi syndrome of the kidney proximal tubules (Lewis et al. 2012). Cataracts are always present at birth, whereas kidney dysfunction is not and may take several months to develop (Jänne et al. 1998). Other symptoms include infantile glaucoma (in ~50% of males), areflexia, seizures, maladaptive behavior, short stature, vitamin-D-resistant rickets, and scoliosis. All affected males have impaired vision (Lewis et al. 2012). Female carriers of Lowe syndrome show no clinical symptoms, however, ~95% do show characteristic lenticular opacities that was absent in all proven noncarriers (Röschinger et al. 2000; Jänne et al. 1998; Lewis et al. 2012).

Dent disease is an X-linked proximal renal tubule dysfunction disorder associated with low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Other symptoms include aminoaciduria, phosphaturia, glycosuria, uricosuria, kaliuresis, impaired urinary acidification, and is occasionally complicated by rickets or osteomalacia. Males in their early childhood (< 10 yrs of age) show the disease phenotype, whereas female carriers may show a milder phenotype. The disease is advanced to end-stage renal disease (ESRD) in 30 to 80% of affected males around 3rd - 5th decades of life. To date, Dent’s disease has been reported in around 250 families (Devuyst and Thakker 2010; Lieske et al. 2012).

Genetics

Lowe syndrome is an X-linked disorder caused by mutations in the OCRL gene. OCRL, which is located on chromosome Xq26.1. encodes phosphatidylinositol 4, 5-biphosphate 5-phosphatase (PIP2P) enzyme, which is localized to trans-Golgi network (TGN) and early endosomes. PIP2P is shown to be required for the clathrin-mediated trafficking between the TGN and early endosomes (Lowe 2005). An alternately spliced OCRL transcript is shown to be expressed in the brain (Sugimoto et al. 2014). PIP2P is highly homologous to inositol polyphosphate 5-phosphatase (INPP5B) and shares 45% sequence identity at the amino acid level and appear to have overlapping functions (Lowe 2005; Attree et al. 1992). Both INPP5B and PIP2P are also localized to the primary cilium and play compensatory roles in ciliogenesis (Luo et al. 2012). The majority of Lowe syndrome patients do not show detectable levels of OCRL mRNA transcripts or phosphatase activity 5 (Lin et al. 1997; Attree et al. 1992), suggesting that causative mutations in OCRL lead to loss-of-function (Satre et al. 1999; Lin et al. 1997; Lin et al. 1998). These studies indicate that Lowe syndrome may represent an inborn error of inositol phosphate metabolism (Lowe). Also, these results suggest that PIP2P assay is an accurate test for Lowe syndrome diagnosis. However, carrier testing is not feasible by this assay due to random X- inactivation in females (Lin et al. 1997). PIP2P is also a Rab effector protein and can bind to a variety of Rab proteins regulate targeted membrane trafficking between organelles (Hou et al. 2011). It has also been shown that the point mutations in OCRL that affects Rab protein binding lead to Lowe syndrome (Hagemann et al. 2012). Somatic and germline mosaicism have been reported in Lowe syndrome (Satre et al. 1999; Monnier et al. 2000). So far, over 150 and 30 causative sequence variations (missense, nonsense, splicing, small and gross insertions and deletions) in OCRL have been associated with Lowe syndrome and Dent disease - 2, respectively (Human Gene Mutation Database). Overall, ~70% of the missense mutations are located in exon 15, and 52% of all mutations are found within exons 11-15 (Satre et al. 1999).

CLCN5 is the main causative gene for Dent disease (accounts for ~ 60% of the cases), whereas mutations in OCRL accounts for only 15% of the cases. OCRL-associated Dent disease (Type 2) is always milder as compared to CLCN5 -associated Dent disease (Type 1) (Lieske et al. 1993).

Clinical Sensitivity - Sequencing with CNV PGxome

OCRL molecular analysis in 9 probands and 26 relatives of Italian origin identified mutations in all nine patients (Addis et al. 2004). Another study indicates that ~ 90% of Lowe syndrome patients have OCRL mutations and new mutations occur in ~32% of the affected males (Sugimoto et al. 2014). Another analysis, which included samples from three probands and their family members (altogether 8 DNA samples), identified OCRL mutations in all probands, and their mothers were carriers of the respective mutations. These mutations were not found in 156 healthy controls (Ke et al. 2012).

Testing Strategy

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

Indications for Test

Candidates for this test are patients with symptoms consistent with Lowe syndrome and Dent disease - 2 (negative for CLCN5 gene pathogenic variants), family members of patients who have known mutations and carrier testing for at-risk family members.

Gene

Official Gene Symbol OMIM ID
OCRL 300535
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Dent Disease 2 XL 300555
Lowe Syndrome XL 309000

Citations

  • Addis M, Loi M, Lepiani C, Cau M, Melis MA. 2004. OCRLMutation analysis in Italian patients with Lowe syndrome. Human Mutation 23: 524–525. PubMed ID: 15108291
  • Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, McInnes RR, Nussbaum RL. 1992. The Lowe’s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 358: 239–242. PubMed ID: 1321346
  • Devuyst O, Thakker RV. 2010. Dent's disease. PubMed ID: 20946626
  • Hagemann N, Hou X, Goody RS, Itzen A, Erdmann KS. 2012. Crystal structure of the Rab binding domain of OCRL1 in complex with Rab8 and functional implications of the OCRL1/Rab8 module for Lowe syndrome. Small GTPases 3: 107–110. PubMed ID: 22790198
  • Human Gene Mutation Database (Bio-base).
  • Jänne PA, Suchy SF, Bernard D, MacDonald M, Crawley J, Grinberg A, Wynshaw-Boris A, Westphal H, Nussbaum RL. 1998. Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. Journal of Clinical Investigation 101: 2042. PubMed ID: 9593760
  • Ke YH, He JW, Fu WZ, Zhang ZL. 2012. Identification of two novel mutations in the OCRL1 gene in two Chinese families with Lowe syndrome. Nephrology (Carlton) 17: 20–25. PubMed ID: 21854507
  • Lewis RA, Nussbaum RL, Brewer ED. 2012. Lowe Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301653
  • Lieske JC, Milliner DS, Beara-Lasic L, Rossetti S. 2012. Dent Disease. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 22876375
  • Lin T, Orrison BM, Leahey AM, Suchy SF, Bernard DJ, Lewis RA, Nussbaum RL. 1997. Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am. J. Hum. Genet. 60: 1384–1388. PubMed ID: 9199559
  • Lin T, Orrison BM, Suchy SF, Lewis RA, Nussbaum RL. 1998. Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients. Mol. Genet. Metab. 64: 58–61. PubMed ID: 9682219
  • Lowe M. 2005. Structure and Function of the Lowe Syndrome Protein OCRL1: Structure and function of OCRL1. Traffic 6: 711–719. PubMed ID: 16101675
  • Luo N, West CC, Murga-Zamalloa CA, Sun L, Anderson RM, Wells CD, Weinreb RN, Travers JB, Khanna H, Sun Y. 2012. OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Human Molecular Genetics 21: 3333–3344. PubMed ID: 22543976
  • Monnier N, Satre V, Lerouge E, Berthoin F, Lunardi J. 2000. OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling. Hum. Mutat. 16: 157–165. PubMed ID: 10923037
  • Röschinger W, Muntau AC, Rudolph G, Roscher AA, Kammerer S. 2000. Carrier assessment in families with lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol. Genet. Metab. 69: 213–222. PubMed ID: 10767176
  • Satre V, Monnier N, Berthoin F, Ayuso C, Joannard A, Jouk PS, Lopez-Pajares I, Megabarne A, Philippe HJ, Plauchu H, Torres ML, Lunardi J. 1999. Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene. Am. J. Hum. Genet. 65: 68–76. PubMed ID: 10364518
  • Sugimoto K, Nishi H, Miyazawa T, Fujita S, Okada M, Takemura T. 2014. A Novel OCRL1 Mutation in a Patient with the Mild Phenotype of Lowe Syndrome. The Tohoku Journal of Experimental Medicine 232: 163–166. PubMed ID: 24614960

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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