CADASIL and CARASIL Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10073 HTRA1 81405,81479 Order Options and Pricing
NOTCH3 81406,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10073Genes x (2)81479 81405, 81406, 81479 $960 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is a disease of the small blood vessels of the brain that ultimately leads to vascular dementia. Two forms of the disease, CADASIL and CARASIL, are distinguished based on the mode of inheritance, genetic defect, and histopathology.

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) was previously referred to as hereditary multi-infarct dementia, chronic familial vascular encephalopathy, and familial subcortical dementia with arteriopathic leukoencephalopathy. It is a primary vascular disease due to the degeneration of vascular smooth muscle cells (VSMC) mainly in the small arteries penetrating the white matter of the brain. The progressive loss of VSMC results in the thickening of the walls of the affected vessels and accumulation of granular osmiophilic material (GOM). This leads to reduced cerebral blood flow and progressive neurological deterioration (Stevens et al. 1977. PubMed ID: 69080; Davous and Fallet-Bianco. 1991. PubMed ID: 1853035).

CADASIL is clinically heterogeneous even among related affected individuals. Symptoms usually begin during the third and fourth decades of life (Chabriat et al. 1995. PubMed ID: 7564728). However, childhood and juvenile onset have been documented (Hartley et al. 2010. PubMed ID: 20197270; Cleves et al. 2010. PubMed ID: 21078731). The most common features are migraine, usually with aura; transient and recurrent subcortical ischemic strokes in the absence of hypertension; gait disturbance; urinary incontinence, psychiatric disturbances ranging from mood changes to severe depression; and progressive cognitive decline characterized by deterioration of executive function and working memory, and eventually dementia (Ruchoux et al. 1995. PubMed ID: 7676806; Lesnik Oberstein et al. 2001. PubMed ID: 11571335; Amberla et al. 2004. PubMed ID: 15143298).

Additional features include acute encephalopathy characterized by confusion, headache, numbness, fever, seizures, and coma; epilepsy; subclinical peripheral neuropathy; and asymptomatic retinal vascular abnormalities. Cardiovascular events have been reported in some patients (Lesnik Oberstein et al. 2003. PubMed ID: 12861102). MRI findings consist of lacunar infarcts and hyperintense lesions that appear first in the subcortical white matter and basal ganglia (Chabriat et al. 1995. PubMed ID: 7564728). Microbleeds have been documented (Choi et al. 2006. PubMed ID: 17135568; Rutten and Lesnik Oberstein 2016. PubMed ID: 20301673).

The prevalence of CADASIL is unknown. However, it has been reported to account for ~11% of cases of lacunar infarcts with coexisting leukoencephalopathy in patients younger than 50 years of age (Dong et al. 2003. PubMed ID: 12511775). CADASIL affects individuals from various ethnic and geographic backgrounds (Ducros et al. 1996. PubMed ID: 8554054).

CARASIL (Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) was previously referred to as Maeda syndrome. The progressive loss of VSMC results in the thickening and splitting of the internal elastic lamina. In CARASIL, there is no accumulation of granular osmiophilic material (GOM) that is characteristic of CADASIL.

Symptoms usually begin during the third decade of life, but later onset have been reported. Most common symptoms include alopecia, ischemic strokes with no hypertension, premature baldness, severe low back pain, personality changes, cognitive deficit and dementia. Additional features include gait disturbance resulting from spasticity of the lower extremities, facial palsy, seizures, convulsions, keratosis, xeroderma, and pigmentary nevus. MRI findings consist of diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus (Fukutake 2011. PMID: 21215656; Nozaki et al. 2014. PMID: 25116877).

CARASIL is rare and affects more males than females. To date about 50 cases have been reported in the literature (Hara et al. 2009. PubMed ID: 19387015; Tikka et al. 2014. PubMed ID: 25323668).

See also Onodera et al. 2014. PubMed ID: 20437615.

Genetics

CADASIL is inherited in an autosomal dominant manner with high penetrance. It is classified in two subtypes, CADASIL1 and 2, based on the genetic cause.

CADASIL1 is caused by pathogenic variants in the NOTCH3 gene (Joutel et al. 1996. PubMed ID: 8878478). CADASIL 2 results from pathogenic variants in the HTRA1 gene (Verdura et al. 2015. PubMed ID: 26063658). CADASIL2 differs from CADASIL1 by a later age of onset, usually during the fifth and sixth decades in life.

NOTCH3 pathogenic variants account for up to 96% of patients fulfilling the diagnostic criteria of CADASIL (Peters et al. 2005. PubMed ID: 16009764). About 300 pathogenic variants have been reported to date. The vast majority are missense variants. They are mostly predicted to result in the gain or loss of cysteine residues in the extracellular domain of the protein. A few small deletions, insertions, indels and splice site variants have been reported. Most of these are expected to result, at the protein level, in inframe deletions that result in an even number of cysteine residues. Two deletions that are predicted to result in a frameshift with premature protein termination have been documented. To date, no large deletions or duplications have been reported (Human Gene Mutation Database).

The great majority of the pathogenic variants are inherited from an affected parent. Although, rare, de novo pathogenic variants have been reported (Joutel et al. 2000. PubMed ID: 10716263; Coto et al. 2006. PubMed ID: 16796587).

NOTCH3 encodes a transmembrane protein that is a member of the NOTCH receptor family. NOTCH signaling is involved in the regulation of various processes in both the embryo and the adult. In adult human tissues, NOTCH3 is expressed exclusively in vascular smooth muscle cells and in pericytes. In CADASIL1, abnormal NOTCH3 protein accumulates on the cell membrane of the VSMCs (Joutel et al. 2000. PubMed ID: 10712431).

To date, 13 missense and one splicing variants in the HTRA1 gene have been reported in several families with a history of autosomal dominant cerebral small vessel disease (CSVD), and features similar to that of NOTCH3-related CADASIL, with no pathogenic variants in NOTCH3 (Verdura et al. 2015. PubMed ID: 26063658; Nozaki et al. 2016. PubMed ID: 27164673). Subsequently, the phenotype was denoted CADASIL2.

CARASIL is inherited in an autosomal recessive manner. It is caused by pathogenic homozygous or compound heterozygous variants in the HTRA1 gene (Hara et al. 2009. PubMed ID: 19387015). Penetrance appears to be incomplete. White matter lesions of various severities have been observed in a number of clinically unaffected parents of CARASIL patients (Bianchi et al. 2014. PubMed ID: 24500651; Chen et al. 2013. PubMed ID: 23963851).

Although alopecia is a hallmark feature of CARASIL, HTRA1 pathogenic variants have been reported in three patients with a clinical diagnosis of CARASIL and no alopecia (Nishimoto et al. 2011. PubMed ID: 21482952; Bianchi et al. 2014. PubMed ID: 24500651).

A total of twelve pathogenic variants have been reported to date, which include 8 missense and 4 truncating variants. No large deletions or duplications have been reported (Human Gene Mutation Database).

HTRA1 pathogenic variants have been reported in patients from various ethnic and geographic backgrounds including Japanese, Chinese, Spanish, Portuguese, Turkish and Romanian (Tikka et al. 2014. PubMed ID: 25323668; Bianchi et al. 2014. PubMed ID: 24500651; Khaleeli et al. 2015. PubMed ID: 25957642; Menezes Cordeiro et al. 2015. PubMed ID: 25712943).

The HTRA1 gene encodes a serine protease that regulates transforming growth factor–beta signaling. In CARASIL, HTRA1 pathogenic variants result in decreased protease activity, which leads to dysregulation of TGF-beta signaling (Hara et al. 2009. PubMed PMID: 19387015). In CADASIL2, HTRA1 variants result in decreased protease activity and in inhibited wild-type HTRA1 activity (Nozaki et al. 2016. PubMed ID: 27164673).

Clinical Sensitivity - Sequencing with CNV PGxome

NOTCH3 pathogenic variants account for up to 96% of patients fulfilling the diagnostic criteria for CADASIL1 (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Type 1) (Peters et al. 2005. PubMed ID: 16009764).

HTRA1 pathogenic variants have been reported in about 5% of patients with a clinical diagnosis of cerebral small vessel disease and no pathogenic variants in the NOTCH3 gene, referred to as CADASIL2 (Nozaki et al. 2016. PubMed ID: 27164673).

Homozygous and compound heterozygous HTRA1 pathogenic variants have been reported in several families with CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), which appears to be rare. To date, about 50 families with a history of the disease have been reported worldwide.

Testing Strategy

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

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Testing should be considered in all patients with a hereditary small vessel disease of unknown etiology (Verdura et al. 2015. PubMed ID: 26063658).

Genes

Official Gene Symbol OMIM ID
HTRA1 602194
NOTCH3 600276
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Amberla et al. 2004. PubMed ID: 15143298
  • Bianchi et al. 2014. PubMed ID: 24500651
  • Chabriat et al. 1995. PubMed ID: 7564728
  • Chen et al. 2013. PubMed ID: 23963851
  • Choi et al. 2006. PubMed ID: 17135568
  • Cleves et al. 2010. PubMed ID: 21078731
  • Coto et al. 2006. PubMed ID: 16796587
  • Davous and Fallet-Bianco. 1991. PubMed ID: 1853035
  • Dong et al. 2003. PubMed ID: 12511775
  • Ducros et al. 1996. PubMed ID: 8554054
  • Fukutake. 2011. PubMed ID: 21215656
  • Hara et al. 2009. PubMed ID: 19387015
  • Hartley et al. 2010. PubMed ID: 20197270
  • Human Gene Mutation Database (Bio-base).
  • Joutel et al. 1996. PubMed ID: 8878478
  • Joutel et al. 2000. PubMed ID: 10712431
  • Khaleeli et al. 2015. PubMed ID: 25957642
  • Lesnik Oberstein et al. 2001. PubMed ID: 11571335
  • Lesnik Oberstein et al. 2003. PubMed ID: 12861102
  • Menezes Cordeiro et al. 2015. PubMed ID: 25712943
  • Nishimoto et al. 2011. PubMed ID: 21482952
  • Nozaki et al. 2014. PubMed ID: 25116877
  • Nozaki et al. 2016. PubMed ID: 27164673
  • Onodera et al. 2014. PubMed ID: 20437615
  • Peters et al. 2005. PubMed ID: 16009764
  • Ruchoux et al. 1995. PubMed ID: 7676806
  • Rutten and Lesnik Oberstein 2016. PubMed ID: 20301673
  • Stevens et al. 1977. PubMed ID: 69080
  • Tikka et al. 2014. PubMed ID: 25323668
  • Verdura et al. 2015. PubMed ID: 26063658

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.

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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