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NOTCH2-Related Disorders via the NOTCH2 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
15259 NOTCH2 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15259NOTCH281479 81479,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

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

  • Stela Berisha, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Dominant-acting defects in the NOTCH2 gene can cause two different clinical conditions: Alagille syndrome and Hajdu-Cheney syndrome (including serpentine fibula-polycystic kidney syndrome). Both are autosomal dominant multisystemic disorders.

Alagille syndrome is characterized by cholestasis (caused by abnormalities in the bile ducts), congenital heart defects (pulmonic stenosis), ophthalmic findings (posterior embryotoxon), vertebral defects (butterfly vertebrae), and characteristic facies (including deep-set eyes with moderate hypertelorism, a broad forehead, a prominent pointed chin, and a long straight nose with a bulbous tip) (Emerick et al. 1999). Symptoms can start from infancy or early childhood. Phenotypes vary greatly among affected individuals even within the same family.

Hajdu-Cheney syndrome is characterized by severe and progressive bone loss throughout the body (Simpson et al. 2011). Patients develop acroosteolysis and generalized osteoporosis over time. Common features include compression fractures of the spinal bones, abnormal curvature of the spine, abnormal long bones in the arms and legs, short stature, abnormal skull bones, and dysmorphic facies. Other variable features include joint and dental abnormalities, hearing loss, renal cysts, excess body hair, and cardiovascular anomalies. Phenotypes vary greatly among affected individuals even within the same family. Of note, serpentine fibula-polycystic kidney syndrome (SFPKS) was once classified as a distinct disease entity, but has been later recognized within the phenotypic spectrum of Hajdu-Cheney syndrome due to clinical and molecular similarities (Gray et al. 2012; Narumi et al. 2013).

Genetics

Alagille syndrome and Hajdu-Cheney syndrome are autosomal dominant disorders caused by defects in the NOTCH2 gene (McDaniell et al. 2006; Isidor et al. 2011; Simpson et al. 2011). The NOTCH2 gene has 34 coding exons that encode Notch2, a member of the Notch family of receptors. Notch2 signaling is important for the development of cells destined to many organs.

Genetic defects in NOTCH2 found to date include missense, nonsense, splicing mutations and small deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving NOTCH2 have not been reported. Pathogenic variants in the NOTCH2 gene can be transmitted within a family or arise de novo.

Alagille syndrome can be caused by different types of NOTCH2 variants throughout the gene. However, Hajdu-Cheney syndrome (including serpentine fibula-polycystic kidney syndrome) is exclusively caused by truncated pathogenic variants clustered in the last exon (near the carboxyl terminus) of the gene. The mutant mRNA products escape nonsense-mediated decay and the resulting truncated Notch2 proteins cause disease through a gain-of-function.

Alagille syndrome is mostly caused by defects in the JAG1 gene, which encodes the Notch signaling pathway ligand Jagged1.

Clinical Sensitivity - Sequencing with CNV PG-Select

NOTCH2 defects are a minor cause of Alagille syndrome, accounting for less than 6% of all cases (McDaniell et al. 2006).

NOTCH2 defects should be detected in near 100% of Hajdu-Cheney syndrome (including serpentine fibula-polycystic kidney syndrome) cases if a clinical diagnosis is strongly indicated.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of most coding exons of the NOTCH2 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.

This test does not include coverage for exons 1 to 4 of the NOTCH2 gene because of high sequence similarity to one or more additional chromosomal regions. So far, no pathogenic variants have been reported in these exons.

Indications for Test

Candidates for this test are patients with Alagille syndrome or Hajdu-Cheney syndrome (including serpentine fibula-polycystic kidney syndrome). Testing is also indicated for family members of patients who have known mutations in the NOTCH2 gene.

Gene

Official Gene Symbol OMIM ID
NOTCH2 600275
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Alagille Syndrome 2 AD 610205
Hajdu-Cheney Syndrome AD 102500

Citations

  • Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. 1999. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29: 822–829. PubMed ID: 10051485
  • Gray MJ, Kim CA, Bertola DR, Arantes PR, Stewart H, Simpson MA, Irving MD, Robertson SP. 2012. Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome. Eur. J. Hum. Genet. 20: 122–124. PubMed ID: 21712856
  • Human Gene Mutation Database (Bio-base).
  • Isidor B, Lindenbaum P, Pichon O, Bézieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Merrer M Le, Mandel J-L, David A, Faivre L, Cormier-Daire V, Redon R, Le Caignec C. 2011. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat. Genet. 43: 306–308. PubMed ID: 21378989
  • McDaniell et al. 2006. PubMed ID: 16773578
  • Narumi Y, Min B-J, Shimizu K, Kazukawa I, Sameshima K, Nakamura K, Kosho T, Rhee Y, Chung Y-S, Kim O-H, Fukushima Y, Park W-Y, Nishimura G. 2013. Clinical consequences in truncating mutations in exon 34 of NOTCH2: report of six patients with Hajdu-Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome. Am. J. Med. Genet. A 161A: 518–526. PubMed ID: 23401378
  • Simpson et al. 2011. PubMed ID: 21378985

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

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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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