Symptoms related to a genetic cause
Hereditary vascular diseases are a broad field of illnesses:
- Venous anomalies with an incidence estimated around 1/10,000
- Capillary malformation that affect ~0.3% of newborns
- Hereditary hemorrhagic telangiectasia with an incidence around 1/10,000
- Cerebral cavernous malformation with a prevalence of about 0.5%
Atherosclerosis is a significant cause of cardiovascular disease; it is a complex multifocal disease of arteries involving interactions of multiple genetic and environmental factors. It is characterized by endothelial dysfunction, vascular inflammation and the buildup of lipids, cholesterol, calcium, and cellular debris within the vessel wall, resulting in plaque formation and vascular insufficiency1. Atherosclerosis incorporates coronary heart disease and stroke, two of the world’s major causes of death, causing 248 deaths per 100,000 people in 2103 representing 85% of cardiovascular deaths2.
- Individuals presenting with the most common symptoms of cardiovascular disease
- Individuals with a positive family history of cardiovascular disease
- Individuals without a positive family history but with symptoms resembling the specific disease indication
- Individuals with a negative, but suspected, family history, in order to perform genetic counseling (prenatal analyses are recommended in families of affected individuals)
Confirmation of a clinical diagnosis through genetic testing allows for genetic counseling and may lead to immediate medical management. For each presented case and phenotype, a full medical report will be produced including a tailored diagnostic strategy, recommendations and a differential diagnosis, if applicable.
Clinical symptoms are not always the product of the same gene or genetic variation; any diagnosis is determined as a combination of the in-depth clinical information provided and the identified genetic cause.
What do we know about vascular diseases?
There are several vascular disorders related to genetic causalities compatible with Mendelian inheritance and multifactorial inheritance. Atherosclerosis, aortic aneurysms and hyperlipidemias are among those entities.
Genetic epidemiologic studies of atherosclerosis have identiﬁed a surprisingly long list of genetic and non-genetic risk factors for coronary artery disease. However, such studies indicate that family history is the most signiﬁcant independent risk factor; most cases of myocardial infarction (MI) and stroke result from the interactions of multiple genetic and environmental factors3. Defining genetic causes of vascular diseases such as atherosclerosis, and their role in risk stratification of coronary artery disease is the most reliable and fastest way of securing the right diagnosis, with direct implications for prevention and familial screening.
Aortic aneurysms, dissections and rupture have ranked as high as the 15th major cause of death in the United States, accounting for nearly 15,000 deaths annually4. Thoracic aortic aneurysms (TAA) tend to be asymptomatic and may not be diagnosed until a catastrophic acute aortic dissection occurs. Seven genes and two loci are known to be associated with TAAD; screening of first-order relatives of probands with TAA is essential5.
One of the most common types of hyperlipidemias occurs due to the mutations in the LDL (low density lipoprotein) receptor gene, familial hypercholesterolemia (FH). This autosomal dominant disorder affects approximately 1 in 500 individuals6. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin, tendons and coronary arteries (atherosclerosis)7.
Testing for vascular diseases
Single Gene Analysis
Antithrombin III deficiency
Aortic aneurysm, familial thoracic type 3
Aortic aneurysm, familial thoracic type 4
Aortic aneurysm, familial thoracic type 5
Aortic aneurysm, familial thoracic type 6
Aortic aneurysm, familial thoracic type 7
Aortic aneurysm, familial thoracic type 8
Aortic aneurysm, familial thoracic, MAT2A related
Aortic valve disease type 1
Aortic valve disease type 2
Arterial calcification type 1, generalized, infantile
Arterial calcification type 2, generalized, infantile
Arterial Tortuosity Syndrome
Atherosclerosis, SOAT1 related
Bernard Soulier syndrome type A1
Bernard Soulier syndrome type A2
Bernard Soulier syndrome type B
Bernard Soulier syndrome type C
Capillary malformation-arteriovenous malformation
Carotid intimal medial thickness type 1
Cerebral cavernous malformations type 1
Cerebral cavernous malformations type 2
Cerebral cavernous malformations type 3
Coarctation of the aorta
Coronary artery disease in familial hypercholesterolemia, protection against
Factor II deficiency
Factor VII deficiency
Glycoprotein Ia C807T polymorphism
Hemorrhagic destruction of the brain, subependymal calcification, and cataracts
Homocystinuria due to cystathionine beta-synthase deficiency
Homocystinuria-megaloblastic anemia, cbl E type
Hypertension early onset
Hypertension, ADD2 related
Hypertension, salt-sensitive essential, susceptibility to
Hypertension, susceptibility to
Loeys-Dietz syndrome type 4
Moyamoya disease type 2, susceptibility to
Moyamoya type 6 with achalasia
Myoglobinuria acute recurrent
Myopathy with lactic acidosis hereditary
Parkes Weber syndrome
Plasminogen activator inhibitor type 1
Polyarteritis nodosa, childhood-onset
Protein C Deficiency, AD
Protein S Deficiency, autosomal dominant
Pseudohypoaldosteronism type 2D
Pseudohypoaldosteronism type 2E
Pulmonary hypertension, primary type
Pulmonary venoocclusive disease type 1
Supravalvar aortic stenosis
Thrombophilia due to thrombin defect
Transposition of the great arteries, dextro-looped 1
Vascular system defects due to CALCRL deficiency
Vascular system defects due to GNA13 deficiency
What can CENTOGENE do for you and your patients?
CENTOGENE is a global leader in the diagnosis of rare genetic diseases and has received multiple international accreditations (ISO/EN 15189, CAP and CLIA) that confirm the highest standards for diagnostic testing and reporting. Our experience, combined with our scientific expertise and medical competence, has allowed the application of state-of-the-art science and technology and the development of a proprietary mutation database.
CENTOGENE has identified genetic variants associated with vascular diseases in more than 60 different genes.
In CentoMD®, the world’s largest mutation database for rare diseases with 57% of unpublished variants, we have carefully created and document all variants that have clinical relevance for related symptoms supporting the precise diagnosis of a bone, skin and immune disease.
- Hadi NR, Mohammad BI, Ajeena IM, Sahib HH. Antiatherosclerotic potential of clopidogrel: antioxidant and anti-inflammatory approaches. BioMed research international. 2013 Dec 26;2013. https://www.hindawi.com/journals/bmri/2013/790263/abs/
- Global, regional, and national ageesex speciﬁc all-cause and cause-speciﬁc mortality for 240 causes of death, 1990e2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385:117e171
- Lusis AJ, Mar R, Pajukanta P. Genetics of atherosclerosis. Annu. Rev. Genomics Hum. Genet.. 2004 Sep 22;5:189-218.
- Hoyert DL, Arias E, Smith BL, Murphy SL, Kochanek KD. Deaths: final data for 1999. Natl Vital Stat Rep. 2001;49(8):1–113
- Albornoz G, Coady MA, Roberts M, Davies RR, Tranquilli M, Rizzo JA, Elefteriades JA. Familial thoracic aortic aneurysms and dissections--incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006;82:1400–5
- Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Human mutation. 1992 Jan 1;1(6):445-66.
- Goldstein JL, Brown MS (1989) Familial hypercholesterolemia. In, The Metabolic Basis of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D (eds): New York: McGraw-Hill, pp 1215-1250.
Scientific Articles on Vascular Diseases
Fabry disease is a multi-system lysosomal storage disorder. As it is caused by an enzyme deficiency, enzyme replacement therapy is the standard treatment option. To overcome some of the issues with this strategy, alternatives are being explored through a collaborative effort involving researchers…
Adiponectin is a hormone with well-known relevance to cardiac and renal function. As Fabry disease (FD), a rare metabolic disorder, often manifests with cardiac and/or renal symptoms, researchers at CENTOGENE examined a potential link to adiponectin. Their finding of plasma adiponectin levels to…
Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway.…
Clinical findings and genetic background of the most prevalent hereditary vascular diseases
|Disease||Gene/Genes||Clinical findings||Prevalence and epidemiology||Onset|
|Aortic aneurism||FBN1, PRKG1, MAT2A, TGFBR2, TGFBR1, MYH11, ACTA2, MYLK, SMAD3 etc.||Asymptomatic or presenting as chest abrupt pain, pallor, pulselessness, paresthesia, stroke, acute myocardial infarction, and paralysis.||15,000 deaths annually 19% affected have a first-degree relative with TAAD||Highly variable age of onset|
|Arterial calcification||Arterial calcification||Arterial calcification and/or narrowing of large- and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly).||Approx. 200 individuals reported so far||Infantile onset|
|Atherosclerosis Coronary artery disease (CAD)||APOB, TNFR1, LDLR, PCSK9, SOAT1 etc.||Chest pain, pain in the arm, shortness of breath, sweating, nausea, heart palpitations||Increasing prevalence, ~28.2% of all-cause mortality||Mostly adult onset|
|Bernard Soulier syndrome Hemorrhagi-thrombocytic dystrophy||GP1BA, GP1BB, GP9||Easy bruising, nosebleeds, purpura and petechial rash, mucosal bleeding, menorrhagia, gastrointestinal bleeding||Less than 1 case per million population||From adolescence to adult onset|
|CADASIL||NOTCH3||NOTCH3||Two and four per 100,000||Mid-adult onset|
|CARASIL||HTRA1||Gait disturbance from spasticity||Only ~10 cases reported||23% have onset >40|
|Cerebral cavernous malformations||KRIT1, CCM2, PDCD10 etc.||Asymptomatic (>50%) or with seizures, focal neurological deficits, headaches, and cerebral hemnorrhage.||0.4%-0.5% of the general population||From early to late onset|
|Fabry disease||GLA||acroparesthesiasAcroparesthesias, angiokeratomas, sweating abnormalities, proteinuria, thrombosis, artery ischemia and aneurysm||1:50,000 males||Childhood and rarely adult onset|
|Hypertension early onset||NR3C2, ADD2, CYP3A5, AGTR1, ATP1B1 etc.||Abnormally high blood pressure, neurological, cardiological and other consequences||50% of the >60 years population overall 20% adults||Adult, rarely early onset|
|Loeys-Dietz syndrome||TGFBR1 (20%), TGFBR2 (70%), SMAD3, TGFB2||Vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations||Rare, less than 1/10,000||From early to late onset|
|Moyamoya disease||RNF213||Asymptomatic to manifesting, severe neurologic deficits, hemorrhage and cerebral ischemic events||0.086 case per 100,000 worldwide 3,16/100,000 in Japan||Adult onset|
|Hemangioma||VEGFR3, PDGFRB, FLT4, VEGFR2, TEM8||Abnormal mostly asymptomatic accumulation of noncancerous blood vessels in skin, liver, kidneys, brain||7.4% prevalence rate||Neonatal, infantile and adult|