• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The ENG gene is associated with autosomal dominant hereditary hemorrhagic telangiectasia (HHT) (MedGen UID: 52657) and hereditary pulmonary arterial hypertension (PAH) (MedGen UID: 57749).

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Pathogenic ENG variants are a rare cause of HHT and are associated with an unknown percentage of clinical cases of JPS.

The ENG gene product acts as TGF-beta coreceptor and is involved in the TGF-beta/BMP signaling cascade. The TGF-beta pathway has been demonstrated to be important in cellular localization and migration. Additionally, ENG is thought to be involved in vascular remodeling.

ENG Heterozygote
OMIM: 131195

Clinical condition
The ENG gene is associated with autosomal dominant hereditary hemorrhagic telangiectasia (HHT) (MedGen UID: 52657) and hereditary pulmonary arterial hypertension (PAH) (MedGen UID: 57749). There is also emerging evidence of an association with autosomal dominant juvenile polyposis syndrome. Therefore, ENG is available as a “preliminary-evidence” gene on the Invitae Colorectal Cancer Panel (PMID: 16287957, 23399955). Preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and this specific cancer condition has not been completely established. This uncertainty may be resolved as new information becomes available, and so in the meantime, clinicians may continue to order these preliminary evidence genes.

HHT is characterized by abnormal blood vessel development resulting in multiple telangiectases and arteriovenous malformations (AVM). AVMs often occur in the lungs, liver, brain, and gastrointestinal tract. The most common clinical manifestation is recurrent nosebleeds (epistaxis) due to telangiectases of the nasal mucosa. The severity of symptoms of HHT are highly variable within and among families and exhibit age-related penetrance (PMID: 20301525, 25674101).

Pulmonary arterial hypertension (PAH) is characterized by high blood pressure (hypertension) in the pulmonary artery due to obstruction and obliteration of the arterioles in the lungs (PMID: 24936649). This results in increased pressure on the pulmonary artery and the right ventricle of the heart. The persistent pressure on the right ventricle can lead to progressive heart failure. Common symptoms associated with PAH include dyspnea, fatigue, syncope, chest pain, palpitations, and leg edema. The heritable forms of PAH are accounted for by familial PAH and simplex PAH (i.e., a single occurrence in a family) (PMID: 20301658).

Gene information
The ENG gene provides instructions for making a protein called endoglin. This protein is found on the surface of cells, especially in the lining of developing arteries. It forms a complex with growth factors and other proteins involved in the development of blood vessels. In particular, this complex is involved in the specialization of new blood vessels into arteries or veins (National Library of Medicine. Genetics Home Reference. ENG. Accessed February 2018.).

Pathogenic variants in ENG have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing that variant on to their offspring. Most cases are inherited, while some are the result of a spontaneous de novo mutation, meaning that an individual with a pathogenic variant has parents who do not have it. However, that individual has a 50% risk of passing it on to offspring.

The following evaluations are recommended to establish the extent of disease in an individual diagnosed with HHT (PMID: 21546842, 19553198):

  • medical history and physical exam with special attention to epistaxis, other bleeding, anemia, polycythemia, telangiectases, and diseases of the heart, lungs, liver, and neurologic system
  • complete blood count and serum ferritin with concentration on anemia (especially disproportionate to epistaxis level), polycythemia, and potential iron supplementation
  • oxygen saturation by pulse oximetry
  • contrast echocardiogram to detect pulmonary arterioveneous shunting and measure pulmonary artery systolic pressure
  • head MRI (with and without gadolinium) in the first 6 months of life or at the time of diagnosis to detect cerebral AVMs
  • if individual has symptoms of hepatic AVM, consider abdominal ultrasound or CT

Women with HHT considering pregnancy should be screened and treated for pulmonary and cerebral AVMs. Affected pregnant women with undetected and/or untreated AVMs (particularly lung AVMs) are at risk for serious complications; therefore, pulmonary AVMs discovered during pregnancy are treated during the second trimester. Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia (PMID: 20301525).

In general, AVMs of the lungs and brain are treated in those without symptoms given their often sudden and catastrophic presentation, but telangiectases of the skin, oral and GI mucosa, and liver are treated when symptoms dictate. Referral to centers with HHT, neurovascular, or otorhinolaryngology expertise is recommended for diagnosis and management (PMID: 21546842, 19553198).

The following treatment and management recommendations for PAH have been suggested by the American College of Cardiology Foundation Board of Trustees and the American Heart Association Science Advisory and Coordinating Committee (PMID: 19389575):

  • implement efforts to lower pulmonary arterial pressure, normalize cardiac output, and enhance functional capacity, as measured objectively by an assessment of exercise endurance
  • encourage low-level graded aerobic exercise, such as walking
    • avoidance of heavy physical exertion or isometric exercise, which may evoke exertional syncope
  • avoid exposure to high altitudes, which may contribute to hypoxic pulmonary vasoconstriction
    • supplemental oxygen on commercial aircraft may be required
  • a sodium restricted diet
  • routine immunizations are advised

The hemodynamic fluctuations of pregnancy, labor, delivery, and the postpartum period are potentially devastating in PAH. Some series have demonstrated a 30% to 50% maternal mortality rate (PMID: 19389575). Current guidelines advise that pregnancy is contraindicated (PMID: 19389575).

In general, distinguishing optimal treatment strategies in PAH broadly depends on the diagnostic categories, hemodynamics, severity of the disease, and associated findings (PMID: 19389575). Referral centers specializing in diagnosis and therapy of PAH are available and are encouraged for high-risk individuals due to the complexity and continuing evolution of diagnosis and treatment (PMID: 19389575).

Because the evidence regarding ENG in association with juvenile polyposis syndrome is limited and preliminary, there are currently no guidelines or recommendations to suggest alteration to medical management based solely on the presence of a pathogenic ENG variant. An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant in ENG is present is advantageous. Relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data is likely to become available in the near future. Awareness of this pathogenic variant allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

Review date: February 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ENG NM_000118.3