FeedbackPolymerase Chain Reaction/Sequencing
Related Tests
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
- Preferred panel for individuals with clinical phenotype of aortic or vascular aneurysm, dissection, or rupture if no single specific diagnosis is strongly suspected
- See Aortopathy Panel, Sequencing and Deletion/Duplication Test Fact Sheet for more information
Polymerase Chain Reaction/Sequencing
Useful when a pathogenic familial variant identifiable by sequencing is known
Variants in the TGFBR1 and TGFBR2 genes cause Loeys-Dietz syndrome (LDS). LDS affects connective tissue throughout the body, causing a wide range of vascular, skeletal, craniofacial, cutaneous, allergic/inflammatory, gastrointestinal, and ocular abnormalities. Quality of life may be significantly affected depending on the type and severity of symptoms. Life expectancy is typically shortened due to aortic or vascular aneurysms.
Indications for Ordering
- Confirm clinical diagnosis of LDS
- Determine if at-risk family members have a TGFBR1 or TGFBR2 gene variant when
- Familial variant is unknown
- Affected relatives are not available for testing
Disease Overview
Incidence
Unknown; seen in all ethnicities
Symptoms
| Vascular |
|
|---|---|
| Musculoskeletal |
|
| Craniofacial |
|
| Cutaneous |
|
- Mean age of death: 26 years due to arterial aneurysms
- Death or uterine rupture from pregnancy in affected individuals: ~50%
- Various clinical presentations have previously been labeled as LDS types 1, 2, and 3
- LDS now recognized as a clinical continuum; affected individuals can have various combinations of phenotypic features
- Diagnosis of LDS is based on clinical findings and/or by identifying a heterozygous pathogenic variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2
Genetics
Genes
TGFBR1 and TGFBR2
Inheritance
Autosomal dominant
Penetrance
Rare examples of nonpenetrance have been observed
De novo Variants
Approximately 75% of affected individuals
Test Interpretation
Sensitivity/Specificity
Results
| Result | Result Description | Interpretive Data |
|---|---|---|
|
Positive |
Pathogenic variant detected in TGFBR1 or TGFBR2 gene |
Confirms a diagnosis of LDS in a symptomatic individual |
|
Negative |
No variant detected in TGFBR1 or TGFBR2 gene |
Reduces risk, but does not exclude a diagnosis of LDS in a symptomatic individual |
|
Inconclusive |
TGFBR1 or TGFBR2 sequence variants of unknown clinical significance may be detected |
|
Limitations
- Diagnostic errors can occur due to rare sequence variations
- Not detected
- Regulatory region and deep intronic variants
- Large deletions/ duplications of TGFBR1 and TGFBR2
- Variants in genes other than TGFBR1 and TGFBR2
References
-
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Meester JAN, Verstraeten A, Schepers D, et al. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann Cardiothorac Surg. 2017;6(6):582-594.
GeneReviews - Loeys-Dietz Syndrome
Loeys BL, Dietz HC. Loeys-Dietz syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2020. [Last Updated: Mar 2018]
23977594
Pomianowski P, Elefteriades JA. The genetics and genomics of thoracic aortic disease. Ann Cardiothorac Surg. 2013;2(3):271-279.
20838339
Van Hemelrijk C, Renard M, Loeys B. The Loeys-Dietz syndrome: an update for the clinician. Curr Opin Cardiol. 2010;25(6):546-551.
Confirm clinical diagnosis of LDS