Loeys-Dietz Syndrome (TGFBR1 and TGFBR2)

Confirm clinical diagnosis of LDS

Related Tests

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
  • Aortic dilation or dissection
  • Arterial aneurysm and tortuosity
Musculoskeletal
  • Scoliosis
  • Arachnodactyly
  • Talipes equinovarus
  • Joint laxity or contracture
  • Pectus excavatum or carinatum
  • Cervical spine malformation and/or instability
Craniofacial
  • Hypertelorism
  • Craniosynostosis
  • Cleft palate/bifid uvula
Cutaneous
  • Translucent, velvety skin
  • Widened/poorly formed scars
  • Easy bruising
  • Striae
  • 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

  • Clinical sensitivity: up to 85% for both TGFBR1 and TGFBR2 
  • Analytical sensitivity/specificity: 99%

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