Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts & Leukoencephalopathy (CADASIL) (NOTCH3)

Description:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon, autosomal dominant disease, though it is the most common cause of hereditary stroke and hereditary vascular dementia in adults. CADASIL syndrome is an adult-onset, disabling systemic condition, characterized by a migraine with aura, recurrent lacunar strokes, progressive cognitive impairment, and psychiatric disorders. The overall prevalence of the disease is unknown in the general population.

The differential diagnosis of CADASIL includes the following conditions:

Acquired Disorders

Sporadic SVD with or without hypertension as the main risk factor
Multiple sclerosis
Primary angiitis of the central nervous system

Inherited Disorders

Fabry disease
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy
Familial SVD caused by heterozygous variants in the HTRA1 gene
Some forms of leukodystrophy

Since the clinical presentation of CADASIL varies, the condition may be confused with multiple sclerosis, Alzheimer dementia, and Binswanger disease. The specific clinical signs and symptoms, along with family history and brain magnetic resonance imaging findings, are extremely important in diagnosing CADASIL. The clinical features and mode of inheritance (autosomal dominant vs. autosomal recessive) help to distinguish CADASIL from other inherited disorders in a differential diagnosis.

When the differential diagnosis includes CADASIL, various diagnostic tests are available:

Genetic testing, by direct sequencing of select exons or of exons 2 through 24 of the NOTCH3 gene. Identification of a NOTCH3 pathogenic variant definitively establishes a diagnosis of CADASIL without the need for additional diagnostic testing (e.g., skin biopsy).
Genetic testing can facilitate the differentiation of NOTCH3-associated cerebral small vessel disease (CSVD) from other CADASIL-like disorders (e.g., HTRA1-associated CSVD and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) (Yuan, 2024).
Immunohistochemistry assay of a skin biopsy sample, using a monoclonal antibody with reactivity against the extracellular domain of the NOTCH3 receptor. Positive immunostaining reveals the accumulation of the NOTCH3 protein in the walls of small blood vessels (Joutel, 2001). Lesnick Oberstein et al estimated the sensitivity and specificity at 85% to 90% and 95% to 100%, respectively, for 2 observers of the test results in a population of patients and controls correlated with clinical, genetic, and magnetic resonance imaging parameters (Lesnik, 2003).
Detection of granular osmiophilic material in the same skin biopsy sample by electron microscopy. The major component of granular osmiophilic material is the ectodomain of the NOTCH3 gene product (Muqtadar, 2012). Granular osmiophilic material accumulates directly in vascular smooth muscle cells and, when present, is considered a hallmark of the disease (del Rio-Espinola, 2009). However, granular osmiophilic material may not be present in all biopsy samples. Sensitivity has been reported as low as 45% and 57% but specificity is generally near or at 100% (Malandrini, 2007; Brulin, 2002; Markus, 2002).
Examination of brain tissue for the presence of granular osmiophilic material was originally described as limited to brain blood vessels (Choi, 2013). Examination of brain biopsy or autopsy after death was an early criterion standard for diagnosis. In some cases, peripheral staining for granular osmiophilic material has been absent even though positive results were seen in brain blood vessels.

Variants in NOTCH3 have been identified as the underlying cause of CADASIL. In almost all cases, the pathogenic variants lead to loss or gain of a cysteine residue that can lead to increased reactivity of the NOTCH3 protein, resulting in ligand-binding and toxic effects (Mosca, 2011).

The NOTCH3 gene is found on chromosome 19p13.2-p13.1 and encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein NOTCH. The NOTCH3 protein consists of 2321 amino acids, primarily expressed in vascular smooth muscle cells, and plays an important role in the control of vascular transduction. It has an extracellular ligand-binding domain of 34 epidermal growth factor (EGF)-like repeats, traverses the membrane once, and has an intracellular domain required for signal transduction (Rutten, 2016 Hack, 2019).

Variants in the NOTCH3 gene have been differentiated into those causative of the CADASIL syndrome (pathogenic variants) and those of uncertain significance. Pathogenic variants affect conserved cysteine residues within 34 EGF-like repeat domains in the extracellular portion of the NOTCH3 protein (Hack, 2019; Donahue, 2004). More than 150 pathogenic variants have been reported in at least 500 pedigrees. NOTCH3 has 33 exons but all CADASIL variants reported to date have occurred in exons 2 to 24, which encode the 34 EGF-like repeats, with strong clustering in exons 3 and 4, which encode EGF receptors 2 to 5 (>40% of variants in >70% of families occur in these exons) (Chabriat, 2009). A study by Hack et al (2023) identified 3 clinically distinct risk categories (high, medium, and low) of NOTCH3 EGF-like repeats using data from CADASIL and population cohorts (N=4221) (Hack, 2023). Some studies have indicated that the clinical variability in CADASIL presentation, particularly about the development of white-matter hyperintensities on magnetic resonance imaging, may be related to genetic modifiers outside the NOTCH3 locus but the specific role of these modifiers is not well-delineated (Opherk, 2014). Dupé et al investigated the phenotypic variability in individuals with CADASIL and found the mutation location in the NOTCH3 gene (n=436) to be strongly related to clinical severity, and found male sex, arterial hypertension, and smoking to be associated with increased disease severity (Dupe, 2023).

The probability that CADASIL is present in an individualized assessment depends on numerous factors such as family history, symptoms, imaging results, and other specialized testing (e.g., skin biopsy). Pescini et al attempted to identify clinical factors that increase the likelihood of a pathogenic variant being present, with increasing likelihood with the presence of 1 or several factors, including a migraine, migraine with aura, transient ischemic attack/stroke, psychiatric disturbance, cognitive decline, leukoencephalopathy (with greater risk for leukoencephalopathy extending to the temporal pole or external capsule), and subcortical infarcts (Pescini, 2012).

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic testing of NOTCH3 is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

Coding

Effective in 2012, there is a Tier 2 Molecular Pathology CPT code to be used for this testing:

81406: Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia).

Policy/
Coverage:

Effective September 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for a NOTCH3 variant to confirm the diagnosis of CADASIL syndrome meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes under the following conditions:

Clinical signs, symptoms, and imaging results are consistent with CADASIL, indicating that the pretest probability of CADASIL is at least in the moderate-to-high range; and
The diagnosis of CADASIL is inconclusive following magnetic resonance imaging.

For individuals who are asymptomatic with a family member (first- and second-degree relative) with a diagnosis of CADASIL syndrome:

If there is a family member with a known variant, targeted genetic testing of the known NOTCH3 familial variant meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes OR
If the family member’s genetic status is unknown, genetic testing of NOTCH 3 meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for a NOTCH3 variant to confirm the diagnosis of CADASIL syndrome in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, genetic testing for NOTCH3 variant to confirm the diagnosis of CADASIL syndrome in all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective October 2020 – August 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Clinical signs, symptoms, and imaging results are consistent with CADASIL, indicating that the pretest probability of CADASIL is at least in the moderate-to-high range; and
The diagnosis of CADASIL is inconclusive following magnetic resonance imaging.

For asymptomatic individuals with a first- or second-degree relative with a diagnosis of CADASIL syndrome and a known NOTCH3 variant, targeted genetic testing of the known NOTCH3 familial variant meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective October 2018

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Clinical signs, symptoms, skin biopsy and imaging results are consistent with CADASIL, indicating that the pretest probability of CADASIL is at least in the moderate-to-high range; and
The diagnosis of CADASIL is inconclusive following alternative methods of testing, including skin biopsy and magnetic resonance imaging.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective October 2017 – October 2018

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for CADASIL meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes under the following conditions:

Clinical signs, symptoms, skin biopsy and imaging results are consistent with CADASIL, indicating that the pretest probability of CADASIL is at least in the moderate-to-high range; and
The diagnosis of CADASIL is inconclusive following alternative methods of testing, including skin biopsy and magnetic resonance imaging.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for CADASIL for any other reason does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes or is considered investigational. Investigational services are exclusions in the member benefit contract.

Effective Prior to October 2017

Genetic testing for CADASIL does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. The proof of presence of this gene mutation does not lead to specific therapy or improved outcomes for persons having this gene.

For contracts without primary coverage criteria, genetic testing for CADASIL is considered investigational and is not covered. Investigational services are exclusions in the member benefit contract.

Rationale:

Currently, no specific clinical treatment for CADASIL has established efficacy. Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families (Muqtadar, 2012; Lesnik, 1992). Four studies were found that addressed the efficacy of potential treatments for CADASIL (Dichgans, 2008; Huang, 2010; Peters, 2007; De Maria, 2014).

Analytic Validity

Limited relevant primary data on analytic validity were identified. The test is generally done by gene sequencing analysis, which is expected to have high analytic validity when performed under optimal conditions.

Fernandez et al described the development of a next-generation sequencing (NGS) protocol for NOTCH3 and HTRA1 genes in 70 patients referred for clinical suspicion of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), all of whom had previously undergone Sanger sequencing of exons 3 and 4 of the NOTCH3 gene (Fernandez, 2015). NOTCH3 mutations were detected in 6 patients on NGS, including 2 mutations previously detected with Sanger sequencing and 4 mutations in exons 6, 11, and 19.

Clinical Validity

Several retrospective and prospective studies have examined the association between NOTCH3 genes and CADASIL (Moscal, 2011; Lee, 2009; Markus, 2002; Choi, 2013; Yin, 2015; Abramycheva, 2015; Peters, 2005; Tikka, 2009; Dotti, 2005; Joutel, 1997). The results of the clinical validity studies demonstrate that a NOTCH3 mutation is found in a high percentage of patients with a clinical diagnosis of CADASIL, with studies reporting a clinical sensitivity of 90% to 100%. Limited data on specificity are from testing small numbers of healthy controls, and no false-positive NOTCH3 mutations have been reported in these populations. The diagnostic yield studies report a variable diagnostic yield, ranging from 10% to 54%. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders.

Clinical Utility

Confirmation of a CADASIL Diagnosis

The clinical specificity of genetic testing for CADASIL is high, and false-positive results have not been reported in studies of clinical validity. Therefore, a positive genetic test in a patient with clinical signs and symptoms of CADASIL is sufficient to confirm the diagnosis with a high degree of certainty. The clinical sensitivity is also relatively high, in the range of 90% to 100% for patients with a clinical diagnosis of CADASIL. This indicates that a negative test reduces the likelihood that CADASIL is present. However, because false-negative tests do occur, a negative test is less definitive in ruling out CADASIL. Whether a negative test is sufficient to rule out CADASIL depends on the pretest likelihood that CADASIL is present.

Summary of Evidence

The evidence for the use of genetic testing for mutations associated with CADASIL syndrome in individuals with suspected CADASIL syndrome includes retrospective and prospective studies evaluating the clinical validity and yield of NOTCH3 mutation testing. Relevant outcomes are overall survival, test accuracy and validity, other test performance measures, changes in reproductive decision making, change in disease status, and morbid events. The clinical validity studies demonstrate that a NOTCH3 mutation is found in a high percentage of patients with a clinical diagnosis of CADASIL, with studies reporting a clinical sensitivity of 90% to 100%. Limited data on specificity is from testing small numbers of healthy controls, and no false-positive NOTCH3 mutations have been reported in these populations. The diagnostic yield studies report a variable diagnostic yield, ranging from 10% to 54%. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders.

There may be potential clinical utility for genetic testing to diagnose CADASIL in patients whose diagnosis cannot be confirmed by other methods (clinical presentation, magnetic resonance imaging [MRI] findings, skin biopsy). However, no direct evidence was identified demonstrating outcome improvements associated with genetic testing for CADASIL. A strong chain of indirect evidence cannot be constructed given the lack of evidence demonstrating the potential for changes in management that might occur following a diagnosis of CADASIL. The evidence is insufficient to determine the effects of the technology on health outcomes.

The evidence for the use of genetic testing for mutations associated with CADASIL syndrome in individuals who are asymptomatic with family members with CADASIL syndrome is limited. Relevant outcomes are overall survival, test accuracy and validity, other test performance measures, changes in reproductive decision making, change in disease status, and morbid events. For asymptomatic family members of an individual with known CADASIL, knowledge of the presence of a pathologic mutation may lead to changes in lifestyle decisions for the affected individual (eg, reproduction, employment). However, the impact of these lifestyle decisions on health outcomes is uncertain, and there are no interventions for asymptomatic individuals that are known to delay or prevent the onset of disease. The evidence is insufficient to determine the effects of the technology on health outcomes.

2016 Update

A literature search was conducted using the MEDLINE database through September 2016. There was no new information identified that would prompt a change in the coverage statement.

2017 Update

A literature search conducted through September 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Maksemous and colleagues published a study targeting next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients (Maksemous, 2016). Patients evaluated were 44 patients with suspected clinical diagnosis of CADASIL previously screened for standard sequencing exons (3, 4) and/or (2, 11, 18, 19) by Sanger sequencing and classified as negative for known pathogenic variants. NOTCH3 Exons custom NGS panel. The results were 6 patients typical CADASIL pathogenic variants identified in 7/44 patients and specificity was not reported.

ONGOING AND UNPUBLISHED CLINICAL TRIALS

A search of ClinicalTrials.gov in September 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

2019 Update

A literature search was conducted through September 2019. There was no new information identified that would prompt a change in the coverage statement.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2020. The key identified literature is summarized below.

In 2020, a European Academy of Neurology Delphi consensus panel on important clinical questions related to management of monogenic cerebral small-vessel disease reports (Mancuso, 2020):

CADASIL can only be definitively confirmed by genetic testing, revealing a NOTCH3 mutation altering the number of cysteines in one of the 34 EGFr domains of the NOTCH3 protein
CADASIL can be established by skin biopsy, but genetic testing should be the first diagnostic line investigation
In the case of a NOTCH3 variant of unknown significance, CADASIL can be confirmed using a skin biopsy for electron microscopy and/or NOTCH3 immunostaining

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through April 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Gorukmez et al reported on a study of 368 individuals with suspected CADASIL based on radiological and clinical findings. NGS testing was done. 30 variants (17 novel) were detected in 44 individuals from 40 families in exons 2 to 24, 25, 31, and 33 (Gorukmez, 2023).

In a 2023 scientific statement, the American Heart Association reviewed the current clinical, genetic, and imaging aspects of CADASIL to provide prevention, management, and therapeutic considerations to support future treatment recommendations (Meschia, 2023). In consideration of when to test for NOTCH3 mutations, they state to "[c]onsider gene testing in patients with small vessel stroke before 55 y[ears] of age with a paucity of vascular risk factors (e.g., normotensive, nondiabetic, nonsmoker) or positive family history of CADASIL."

CPT/HCPCS:

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), full gene sequence BTK (Bruton agammaglobulinemia tyrosine kinase) (eg, X-linked agammaglobulinemia), full gene sequence CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) (eg, Brugada syndrome), full gene sequence CAPN3 (calpain 3) (eg, limb-girdle muscular dystrophy [LGMD] type 2A, calpainopathy), full gene sequence CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), full gene sequence CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), full gene sequence CLCN1 (chloride channel 1, skeletal muscle) (eg, myotonia congenita), full gene sequence CLCNKB (chloride channel, voltage-sensitive Kb) (eg, Bartter syndrome 3 and 4b), full gene sequence CNTNAP2 (contactin-associated protein-like 2) (eg, Pitt-Hopkins-like syndrome 1), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), duplication/deletion analysis CPT1A (carnitine palmitoyltransferase 1A [liver]) (eg, carnitine palmitoyltransferase 1A [CPT1A] deficiency), full gene sequence CRB1 (crumbs homolog 1 [Drosophila]) (eg, Leber congenital amaurosis), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), duplication/deletion analysis DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence DLAT (dihydrolipoamide S-acetyltransferase) (eg, pyruvate dehydrogenase E2 deficiency), full gene sequence DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence EFHC1 (EF-hand domain [C-terminal] containing 1) (eg, juvenile myoclonic epilepsy), full gene sequence EIF2B3 (eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B4 (eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence ENG (endoglin) (eg, hereditary hemorrhagic telangiectasia, type 1), full gene sequence EYA1 (eyes absent homolog 1 [Drosophila]) (eg, branchio-oto-renal [BOR] spectrum disorders), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), duplication/deletion analysis FAH (fumarylacetoacetate hydrolase [fumarylacetoacetase]) (eg, tyrosinemia, type 1), full gene sequence FASTKD2 (FAST kinase domains 2) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (eg, Charcot-Marie-Tooth disease), full gene sequence FTSJ1 (FtsJ RNA methyltransferase homolog 1 [E. coli]) (eg, X-linked mental retardation 9), full gene sequence FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence GCDH (glutaryl-CoA dehydrogenase) (eg, glutaricacidemia type 1), full gene sequence GCK (glucokinase [hexokinase 4]) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence GLUD1 (glutamate dehydrogenase 1) (eg, familial hyperinsulinism), full gene sequence GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) (eg, inclusion body myopathy 2 [IBM2], Nonaka myopathy), full gene sequence GRN (granulin) (eg, frontotemporal dementia), full gene sequence HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein] alpha subunit) (eg, long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein], beta subunit) (eg, trifunctional protein deficiency), full gene sequence HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence HLCS (HLCS holocarboxylase synthetase) (eg, holocarboxylase synthetase deficiency), full gene sequence HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence HNF4A (hepatocyte nuclear factor 4, alpha) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence IDUA (iduronidase, alpha-L-) (eg, mucopolysaccharidosis type I), full gene sequence INF2 (inverted formin, FH2 and WH2 domain containing) (eg, focal segmental glomerulosclerosis), full gene sequence IVD (isovaleryl-CoA dehydrogenase) (eg, isovaleric acidemia), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), duplication/deletion analysis JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) (eg, epileptic encephalopathy), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence LDLR (low den

References:

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Annunen-Rasila J, Finnila S, et al.(2006) Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL. Neurogentics 2006; [Epub ahead print].

Brulin P, Godfraind C, Leteurtre E, et al.(2002) Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications. Acta Neuropathol. Sep 2002; 104(3): 241-8. PMID 12172909

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Charlton RA, Morris RG, et al.(2006) The cognitive profiles of CADASIL and sporadic small vessel disease. Neurology 2006; 66:1523-6.

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Cumurciuc R, Henry P, et al.(2006) Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study. Stroke 2006; 37:100-2.

De Maria R, Campolo J, Frontali M, et al.(2014) Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL: A Randomized Controlled Trial. Stroke. Sep 2 2014. PMID 25184356

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