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Intellectual Disability via the CRBN 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
9813 CRBN 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9813CRBN81479 81479,81479 $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

  • Renee Bend, PhD

Clinical Features and Genetics

Clinical Features

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD). Nonsyndromic ID is defined by the presence of intellectual disability as the sole clinical feature; however, often times the distinction between syndromic and nonsyndromic ID remains extremely difficult due to the subtle signs of syndromic ID (Kaufman et al. 2010. PubMed ID: 21124998).

Deficiency of cereblon (CRBN) protease leads to autosomal recessive mental retardation 2 (MRT2) (Xu et al. 2013. PubMed ID: 23983124). MRT2 can be nonsyndromic as well as syndromic and the variable clinical features include (but may not be limited to) intellectual disability, developmental delay, delayed or absent speech, motor delay, febrile seizures, intractable seizures, microcephaly, brain malformations, hypotonia, gait abnormalities, feeding difficulties, growth retardation, strabismus, cutaneous and genital anomalies, dysmorphic features such as synophris, hypotelorism, high nasal bridge, thin lips, micrognatia, high palate, large ears, smiling appearance and behavioral abnormalities including attention deficit hyperactivity disorder, aggressiveness, communication difficulties, and self-mutilating behavior (Higgins et al. 2000. PubMed ID: 10932263; Higgins et al. 2004. PubMed ID: 15151510; Higgins et al. 2004. PubMed ID: 15557513; Reuter et al. 2017. PubMed ID: 28097321; Papuc et al. 2015. PubMed ID: 25858704; Sheereen et al. 2017. PubMed ID: 28143899). Of note, at least one patient has been reported with abnormal levels of calcium and uric acids. Female patients tend to display a milder phenotype than males.

Genetics

Mental retardation, autosomal recessive 2 (MRT2) is a neurodevelopmental disorder that results from biallelelic pathogenic variants in CRBN. CRBN consists of 11 coding exons, maps to chromosome 3p26.2, and encodes a 442 amino acid polypeptide. CRBN, primarily expressed in human hippocampus, is an ATP-dependent LON protease and a part of an E3 ubiquitin ligase complex CRL4CRBN. CRBN contains a LON (DNA-binding ATP-dependent protease La) domain and a CULT (CRBN domain of unknown activity, binding cellular ligands and thalidomide) domain and is known to play a role in memory and learning by regulating the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels (Sheereen et al. 2017. PubMed ID: 28143899). To date, nonsense, missense and splice site pathogenic variants have been reported and there are also reports of gross duplications involving CRBN (Human Gene Mutation Database). The disease transmission pattern is consistent with autosomal recessive inheritance.

Clinical Sensitivity - Sequencing with CNV PGxome

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). We expect the analytical sensitivity of the CRBN single nucleotide variants to be high.

To date, two causative gross duplications involving CRBN have been reported (Papuc et al. 2015. PubMed ID: 25858704).

Testing Strategy

This test provides full coverage of all coding exons of the CRBN 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

The primary indication for this test is screening the partners of known carriers of pathogenic variants in couples planning reproduction or couples already pregnant. A panel (or exome/genome) sequencing test would nearly always be more appropriate for patients with ID, unless clinical and/or biochemical evidence points very clearly to the CRBN gene. Targeted Sanger sequencing in this gene is appropriate for carrier testing in family members of patients with CRBN pathogenic variants. Prenatal diagnosis is also possible, if the genetic diagnosis has been firmly established in an affected family member.

Gene

Official Gene Symbol OMIM ID
CRBN 609262
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mental Retardation, Autosomal Recessive 2 AR 607417

Citations

  • Higgins et al. 2000. PubMed ID: 10932263
  • Higgins et al. 2004. PubMed ID: 15557513
  • Higgins et al. 2004. PubMed ID: 15151510
  • Human Gene Mutation Database (Bio-base).
  • Kaufman et al. 2010. PubMed ID: 21124998
  • Papuc et al. 2015. PubMed ID: 25858704
  • Reuter et al. 2017. PubMed ID: 28097321
  • Sheereen et al. 2017. PubMed ID: 28143899
  • Vissers et al. 2016. PubMed ID: 26503795
  • Xu et al. 2013. PubMed ID: 23983124

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.
Total Price: $
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