CADASIL2 and CARASIL via the HTRA1 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
11381 HTRA1 81405 81405,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11381HTRA181405 81405, 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.

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.

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 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

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).

CADASIL is classified in two subtypes, CADASIL1 and 2, based on the genetic cause.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) was previously referred to as Maeda syndrome. It is a disease of the small blood vessels of the brain that ultimately leads to vascular dementia. The progressive loss of vascular smooth muscle cells (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 (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).

Symptoms usually begin during the second and third decades of life. 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.

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).

Pathogenic variants in the HTRA1 have been reported in CARASIL 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 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 patients, 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

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 provides full coverage of all coding exons of the HTRA1 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.

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

It has been suggested that screening for HTRA1 pathogenic variants should be considered in all patients with a hereditary small vessel disease of unknown etiology (Verdura et al. 2015. PubMed ID: 26063658). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in HTRA1.

Gene

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

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
  • 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
  • Khaleeli et al. 2015. PubMed ID: 25957642
  • Lesnik Oberstein et al. 2001. PubMed ID: 11571335
  • Lesnik Oberstein et al. 2003. PubMed ID: 12861102
  • Menezes 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
  • Ruchoux et al. 1995. PubMed ID: 7676806
  • Rutten and Lesnik Oberstein 2016. PubMed ID: 20301673
  • Rutten et al. 2013. PubMed ID: 24000151
  • 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


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