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HTRA1 Disorder

Synonym: CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

, MD, PhD, , MD, PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: November 7, 2019.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

HTRA1 disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) phenotype. Those who have a heterozygous HTRA1 pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL. In this chapter, the term "classic CARASIL" refers to the more severe phenotype associated with biallelic pathogenic variants, and "HTRA1 cerebral small vessel disease" (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant.

  • Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years. Forty-four percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly following the onset of neurologic symptoms. Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic.
  • The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction. A majority of affected individuals have a stroke-like episode after age 40 years. Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD.

Diagnosis/testing.

The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous or biallelic pathogenic variant(s) in HTRA1 on molecular genetic testing.

Management.

Treatment of manifestations: Consideration of anti-platelet therapy and anti-hypertensive therapy for those with cerebral microbleeds; physical therapy, walking aids, and home adaptations for those with gait disturbance; consideration of medication (baclofen or tizanidine) for spasticity; wig or hairpiece for those with alopecia; standard treatment for spinal spondylosis and mood disorder; supportive care including emotional support and counseling for affected individuals and their families.

Surveillance: Follow-up intervals are based on the severity and type of symptoms and the needs of the individuals and their caregivers.

Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis.

Genetic counseling.

HTRA1 disorder caused by biallelic pathogenic variants (i.e., the classic CARASIL phenotype) is inherited in an autosomal recessive manner. HTRA1 disorder caused by heterozygous pathogenic variants is inherited in an autosomal dominant manner.

  • Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of inheriting both HTRA1 pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for HTRA1 disorder.
  • Autosomal dominant inheritance. Each sib of an affected individual has a 50% risk of inheriting the pathogenic variant from their affected parent.

Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HTRA1 disorder are possible.

GeneReview Scope

HTRA1 Disorder: Included Phenotypes
  • Classic CARASIL
  • HTRA1 cerebral small vessel disease (HTRA1-CSVD)

For synonym s and outdated names see Nomenclature.

Diagnosis

Clinical diagnostic criteria for HTRA1 disorder, including the classic CARASIL phenotype ("classic CARASIL"), have not been published.

Suggestive Findings

HTRA1 disorder should be suspected in individuals with the following clinical, neuroimaging, and family history findings.

Clinical features. Individuals presenting before age 55 years with the following:

Note: Those with a heterozygous HTRA1 pathogenic variant (HTRA1 cerebral small vessel disease) may present with these features after age 55 years.

Additional young adult-onset findings in those with biallelic pathogenic variants in HTRA1 (classic CARASIL):

  • Spondylosis deformans. Acute mid- to lower-back pain (lumbago) associated with spondylosis and disk degeneration with osteophyte formation in the lumbar spine
  • Alopecia. Typically seen before age 30 years
    Note: Alopecia is variable; affected individuals with biallelic HTRA1 pathogenic variants without alopecia have been reported [Nishimoto et al 2011, Nozaki et al 2014].

Neuroimaging. Extended white matter lesions and external capsule lesions:

  • Early-onset leukoaraiosis (changes in deep white matter in the brain, observed on MRI or CT). Leukoaraiosis may precede neurologic symptoms [Fukutake 2011, Nozaki et al 2015].
  • Brain MRI resembling that of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Findings in symptomatic individuals may include the following [Fukutake 2011, Nozaki et al 2015]:
    • Symmetrically distributed white matter hyperintensities located in the periventricular and deep white matter
      Note: White matter changes may precede the onset of neurologic symptoms, including gait disturbance, mood change, and cognitive decline.
    • T2-weighted signal abnormalities in the white matter of the anterior part of the temporal lobe, cerebellum, brain stem, and middle cerebellar peduncle (arc sign), and in the external capsule
    • Relative preservation of U-fibers
    • Lacunar infarcts (linearly arranged groups of rounded and circumscribed lesions with signal intensity identical to that of cerebrospinal fluid) in the basal ganglia and subcortical white matter
    • Microbleeds in the cerebral cortex, basal ganglia, brain stem, and cerebellum
      Note: It is not clear if the white matter changes in the anterior temporal poles and external capsule, which are characteristic signs in CADASIL, are also observed in early stages of CARASIL.

Family history consistent with:

  • Autosomal recessive inheritance in those with classic CARASIL
  • Autosomal dominant inheritance for those with a heterozygous HTRA1 pathogenic variant (HTRA1-CSVD)

Note: Absence of a known family history of HTRA1 disorder does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous pathogenic variant or biallelic pathogenic variants in HTRA1 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of HTRA1 disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CARASIL has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and imaging findings suggest the diagnosis of classic CARASIL, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of HTRA1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Given the mechanism of disease causation (see Molecular Genetics), it is unclear whether exon or whole-gene deletions/duplications cause this phenotype.
  • A cerebral small vessel disease multigene panel that includes HTRA1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of CARASIL or HTRA1 disorder is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in HTRA1 Disorder

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
HTRA1Sequence analysis 3Estimated >95% 4
Gene-targeted deletion/
duplication analysis 5
Unknown 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

HTRA1 disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe classic CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) phenotype. Those who have a heterozygous HTRA1 pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL [Verdura et al 2015, Nozaki et al 2016].

HATR1 Disorder Caused by Biallelic HATR1 Pathogenic Variants (Classic CARASIL)

Neurologic symptoms begin between ages 20 and 50 years.

  • The most frequent initial symptom is slowly progressive gait disturbance from spasticity and pyramidal signs in the lower extremities beginning between ages 20 and 40 years.
  • Mood change (depression and irritability) and cognitive dysfunction begin between ages 20 and 50 years.
  • Pseudobulbar palsy also begins between ages 30 and 50 years.
  • Forty-four percent of affected individuals have a stroke-like episode (e.g., hemiparesis or hemisensory impairment) before age 40 years.
  • The disease progresses slowly following the onset of neurologic symptoms. In the advanced stage, emotional incontinence, abulia, and akinetic mutism develop.

Spondylosis (disk degeneration with osteophyte formation), which typically follows acute lower- and mid-back pain (lumbago), results in lower-limb pain beginning between ages ten and 30 years. Severe spondylosis deformans with osteoporosis in the cervical and lumbar spine [Nozaki et al 2015] and deformity and formation of osseous specula in the knee joints [Yanagawa et al 2002] may be appreciated on plain radiographs.

Alopecia is frequently (not always) seen before age 30 years.

  • Scalp alopecia is diffuse, not confined to the frontal or parietal regions.
  • There is no obvious body hair loss.

Pathology. From the autopsy findings, arteriosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth muscle cells, and hyaline degeneration of the media have been observed in cerebral small arteries. These pathologic findings resemble those observed in persons with non-hereditary ischemic cerebral small vessel disease [Okeda et al 2004, Oide et al 2008, Ito et al 2016]. However, multilayering and splitting of elastic laminae may be specific for CARASIL. These changes are predominant in cerebral small arteries; therefore, skin biopsy is not useful for diagnosis.

Note: Granular osmiophilic material within the vascular media close to smooth muscle cells, a pathologic hallmark for CADASIL, is never observed in CARASIL.

HTRA1 Disorder Caused by a Heterozygous Pathogenic Variant (HTRA1 Cerebral Small Vessel Disease)

Neurologic symptoms typically begin after age 40 years [Nozaki et al 2016] and include the following:

  • Slowly progressive gait disturbance (the most frequent initial symptom)
  • Mood change (depression and irritability) and cognitive dysfunction
  • A stroke-like episode (e.g., hemiparesis or hemisensory impairment) in 63% of affected individuals
  • Slow progression of the disease following the onset of neurologic symptoms

Spondylosis and alopecia are rarer findings.

  • Spondylosis deformans is seen in about 36% of affected individuals.
  • Alopecia is seen in about 20% of affected individuals.

Pathology. Small vessels in the central nervous system have shown intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. The features resemble those of individuals with classic CARASIL [Nozaki et al 2016, Ito et al 2018].

Genotype-Phenotype Correlations

No strong genotype-phenotype correlations for HTRA1 have been identified in classic CARASIL [Hara et al 2009, Favaretto et al 2019].

Those who have a heterozygous HTRA1 missense variant that either leads to defective trimerization or is located in the LD or L3 domain may have a more severe phenotype than those who have a heterozygous HTRA1 loss-of-function variant [Nozaki et al 2016, Uemura et al 2019].

Nomenclature

Other names for HTRA1 disorder include the following:

  • CARASIL, for those who have biallelic HTRA1 pathogenic variants
  • Familial young adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension
  • Nemoto disease
  • Maeda syndrome
  • CADASIL2 (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2; OMIM 616779)

Prevalence

HTRA1 disorder has been reported in individuals from Asia, Europe, and North America. However, no founder haplotype has been identified; thus, the authors suspect that the disease will be found more widely.

Differential Diagnosis

Other inherited disorders that cause leukoaraiosis in adulthood are summarized in Table 2. They can be distinguished from HTRA1 disorder by clinical signs, MRI findings, and appropriate laboratory investigations.

Note: Classic CARASIL should be considered in any young person who has alopecia in conjunction with multiple white matter lesions on MRI.

Table 2.

Inherited Disorders with Adult-Onset Leukoaraiosis to Consider in the Differential Diagnosis of HTRA1 Disorder

Gene(s)DisorderMOIClinical Description
COL4A1, COL4A2COL4A1- & COL4A2-related small vessel disease (see COL4A1-Related Disorders)AD
  • Intracranial aneurysm
  • Renal abnormalities (hematuria, cystic kidney)
  • Muscle cramps
  • Retinal arteriolar tortuosity (retinal hemorrhages)
CTSACARASALADTherapy-resistant hypertension 1
GLAFabry diseaseXL
  • Periodic severe pain in extremities
  • Angiokeratoma
  • Renal insufficiency
  • Hypohidrosis
  • Left ventricular hypertrophy
  • Corneal opacities
ITM2BFamilial British dementia (OMIM 176500)ADAtaxia, spasticity
NOTCH3CADASIL 2, 3ADIsolated T2-weighted hyperintensities involving temporal poles on brain MRI
TREX1HERNS (OMIM 192315)AD
  • Contrast-enhancing lesion mimicking tumor on brain MRI
  • Retinal artery abnormalities (macular capillary dropout, tortuous telangiectasia)
  • Progressive visual loss
  • Raynaud phenomenon
  • Migraine
  • Proteinuria & hematuria

AD = autosomal dominant; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL = cathepsin A-related arteriopathy with strokes and leukoencephalopathy; HERNS = hereditary endotheliopathy with retinopathy, nephropathy, and stroke; MOI = mode of inheritance; XL = X-linked

1.
2.
3.

Recommended laboratory investigations: skin biopsy evaluation for NOTCH3 protein expression and electron microscopy for granular osmophilic material

Other. The clinical characteristics and MRI abnormalities in the following conditions may also resemble those of CARASIL:

  • Small vessel diseases (e.g., familial SVD, Portuguese-French type [Verreault et al [2006])
  • Swedish hereditary multi-infarct dementia [Low et al 2007]
  • Sporadic small vessel diseases including Binswanger disease and primary angiitis of the nervous system (Binswanger disease can be distinguished from CARASIL by the presence of hypertension.)

Management

Consensus clinical management guidelines for HTRA1 disorder, including classic CARASIL, have not been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HTRA1 disorder, the evaluations summarized in Table (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with HTRA1 Disorder

System/ConcernEvaluationComment
NeurologicNeurologic evaluationIncl scales to evaluate severity of gait disturbance & pseudobulbar palsy
T2*-weighted gradient echo imagingTo evaluate for cerebral microbleeds
PsychiatricNeuropsychiatric evaluationTo screen for anxiety, mood disturbance, & cognitive dysfunction
GastrointestinalConsider feeding &/or swallowing study.If there is concern for pseudobulbar palsy
SkeletalConsider MRI of spine.To evaluate for degenerative changes in lumbar or cervical spine
DermatologicAssessment for scalp alopecia
Miscellaneous/
Other
Consultation w/clinical geneticist &/or genetic counselorIncl genetic counseling
Family supports/resources

Treatment of Manifestations

Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.

Table 4.

Treatment of Manifestations in Individuals with HTRA1 Disorder

Manifestation/ConcernTreatmentConsiderations/Other
Cerebral microbleedsAnti-platelet therapy & anti-hypertension therapy may be considered.There is no evidence for their effectiveness.
Gait disturbancePhysical therapy to ameliorate coordination difficulties, especially w/walking
Crutches (less often canes) & walkersTo prevent falls
Home adaptations incl grab bars for bathtub or shower chairs, raised toilet seats, & ramps to accommodate motorized chairs, as needed
Medication (e.g., baclofen, tizanidine)May be considered for those w/spasticity
Mood disorderStandard treatment per psychiatristPersonality changes may necessitate antipsychotic medication.
Pseudobulbar palsySpeech/language therapyCommunication devices such as writing pads & computer-based devices may also be of benefit.
Video esophagrams can identify consistency of food least likely to trigger aspiration.Weighted eating utensils & dressing hooks help maintain a sense of independence.
Spinal spondylosisStandard treatment per orthopedistFor those w/neurologic deficits due to spinal compression
AlopeciaWig or hairpiece
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment for need of home nursing

Surveillance

The interval at which a person with HTRA1 disorder is followed depends on the severity and type of symptoms and the needs of the affected individual and caregivers.

Agents/Circumstances to Avoid

Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis, should be avoided.

Evaluation of Relatives at Risk

It has been speculated that hypertension or smoking may influence the age of onset and frequency of stroke episodes in individuals with HTRA1 disorder; smoking may result in earlier disease onset [Singhal et al 2004], and smoking or hypertension may increase the frequency of stroke episodes in individuals with the classic CADASIL phenotype [Adib-Samii et al 2010]. Therefore, it is appropriate to test the older and younger sibs of a proband for presence of the HTRA1 pathogenic variant(s) in the family in order to identify early in adulthood (ideally at age ≥18 years) those who would benefit from initiation of treatment and preventive measures such as oral administration of anti-hypertensive drugs and abstinence from smoking.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

HTRA1 disorder caused by biallelic pathogenic variants (classic CARASIL) is inherited in an autosomal recessive manner.

HTRA1 disorder caused by a heterozygous pathogenic variant (HTRA1-CSVD) is inherited in an autosomal dominant manner.

Autosomal Recessive Inheritance

Risk to Family Members

Parents of a proband

Sibs of a proband

  • If each parent is known to be heterozygous for an HTRA1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both HTRA1 pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for HTRA1 disorder.
  • It is not clear whether carriers (heterozygotes) are asymptomatic (see Parents of a proband).

Offspring of a proband. The offspring of an individual with biallelic pathogenic variants are obligate heterozygotes for one HTRA1 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for one HTRA1 pathogenic variant.

Heterozygote Detection

Molecular genetic testing for at-risk family members requires prior identification of the HTRA1 pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with autosomal dominant HTRA1 disorder have an affected parent.
  • Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if a pathogenic variant occurred de novo, the proportion of HTRA1 disorder caused by a de novo pathogenic variant is unknown. (To date, de novo pathogenic variants have not been reported in HTRA1 disorder.)
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.
  • The family history of some individuals diagnosed with HTRA1 disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with autosomal dominant HTRA1 disorder has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the HTRA1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is possible once the HTRA1 pathogenic variant(s) have been identified in an affected family member.
  • Potential consequences of such testing including (but not limited to) socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing – should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

  • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of HTRA1 disorder, it is appropriate to consider testing symptomatic individuals regardless of age.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being affected or of being heterozygous.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing for HTRA1 disorder are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

HTRA1 Disorder: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
HTRA110q26​.13Serine protease HTRA1HTRA1 databaseHTRA1HTRA1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for HTRA1 Disorder (View All in OMIM)

600142CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY; CARASIL
602194HTRA SERINE PEPTIDASE 1; HTRA1
616779CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2; CADASIL2

Molecular Pathogenesis

Introduction. HTRA1 belongs to the HTRA protein family, the members of which have dual roles as chaperones and serine proteases [Clausen et al 2002]. They serve as stress sensors for unfolded proteins and repress transforming growth factor-beta (TGF-β) family signaling [Clausen et al 2002, Oka et al 2004]. HTRA1 proteins exist as trimers, thus allowing communication between adjacent subunits to regulate protease activity [Truebestein et al 2011].

In vitro functional expression studies with HTRA1 known pathogenic variants showed a loss of protease activity and consequent inability to repress TGF-β family signaling [Hara et al 2009]. Additionally, the mutated HTRA1 proteins of some pathogenic variants show a dominant-negative effect by interfering with communication between adjacent subunits [Nozaki et al 2016, Uemura et al 2019].

Mechanism of disease causation. Loss of function. Some pathogenic variants have a dominant-negative effect [Hara et al 2009, Nozaki et al 2016, Uemura et al 2019].

References

Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 10-29-19. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2018. Accessed 10-29-19.

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Chapter Notes

Revision History

  • 7 November 2019 (ma) Comprehensive update posted live
  • 11 September 2014 (me) Comprehensive update posted live
  • 17 February 2011 (cd) Revision: prenatal testing available clinically
  • 27 April 2010 (me) Review posted live
  • 5 January 2010 (oo) Original submission
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