Loeys-Dietz syndrome (LDS)

Loeys-Dietz syndrome (LDS) is a systemic connective tissue disorder caused by mutations in the TGFBR1 or TGFBR2 genes (also available as part of the 16 gene Marfan syndrome/TAAD sequencing panel). The skeletal features of Loeys-Dietz syndrome, such as joint laxity, arachnodactyly, pectus deformity, and scoliosis, can overlap with the Marfan phenotype, however most individuals with LDS have features in other organ systems not typical of Marfan syndrome (Loeys 2005). Patients with Loeys-Dietz syndrome can exhibit various craniofacial, neurodevelopmental, skeletal and skin abnormalties, however features specific to LDS include hypertelorism, cleft palate or bifid uvula, and arterial or aortic aneurysms and aterial tortuosity (Van Hemelrijk 2010). The primary risk for early mortality is due to aterial tortuosity and/or aortic root dilatation, which results in an increased risk of aterial or aortic aneurysm (Van Hemelrijk 2010). Since patients with LDS can develop potentially lethal arterial aneurysms that would not be detected by echocardiogram, differentiating between Loeys-Dietz and Marfan syndromes is necessary to determine the appropriate clinical management. Similar to Marfan syndrome, genetic testing is important for identifying presymptomatic family members at risk for developing Loeys-Dietz syndrome.Mutations in the FBN1 gene have also been observed in families with isolated ectopia lentis and MASS syndrome (myopia, mitral valve prolapse, borderline/non-progressive aortic root dilation, skeletal and skin findings). MASS is a connective tissue disorder related to Marfan syndrome but with milder cardiovascular findings.

Tests Available

Forms and Documents

Test Details

TGFBR1, TGFBR2
  • Confirmation of a clinical diagnosis
  • Differentiation of a fibrillinopathy (including Marfan syndrome) from related connective tissue disorders such as Loeys-Dietz syndrome, and Ehlers-Danlos syndrome vascular type
  • Presymptomatic testing; Identification of family members at risk for Marfan syndrome to allow for appropriate screening and management
  • Recurrence risk assessment
  • Prenatal diagnosis in families with a known mutation in the TGFBR1 or TGFBR2 genes
  • Capillary Sequencing

Ordering

511
8-9 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Buccal Swabs

Billing

81405x2
No
Yes
  • 441.9 Aortic aneurysm of unspecified site without mention of rupture Aneurysm Dilatation of aorta, Hyaline necrosis of aorta
  • 441.5 Aortic aneurysm of unspecified site, ruptured Rupture of aorta NOS
  • 759.82 Marfan syndrome
  • 512.8 Other spontaneous pneumothorax Pneumothorax
  • 754.81 Pectus excavatum Congenital funnel chest
  • 737.43 Scoliosis
  • 701.3 Striae atrophicae, Atrophic spots of skin, Atrophoderma maculatum, Atrophy blanche (of Milian), Degenerative colloid atrophy, Senile degenerative atrophy, Striae distensae
  • 379.32 Subluxation of lens
  • 441.00 Unspecified site
* For price inquiries please email zebras@genedx.com

References

  1. Goudie DR et al. Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGRBR1. Nat Genet 43:365-369, 2011.
  2. de Paepe A et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 62:417-426, 1996. Loeys BL The revised Ghent Nosology for the Marfan syndrome. J Med Genet 47:476-485, 2010.
  3. Loeys BL et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37(3):275-281, 2005.
  4. Van Hemelrijk C et al. The Loeys-Dietz syndrome: An update for the clinician. Curr Opin Cardiol 25:546-551, 2010.
  5. Boileau C et al. Molecular genetics of Marfan syndrome. Curr Opin Cardiol. 20:194-200, 2005.
  6. Arbustini E et al. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. Hum Mut. 26:494-509, 2005.
  7. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 17:1121-1128, 2009.
  8. Akutsu K et al. Genetic analysis of young adult patients with aortic disease not fulfilling the diagnostic criteria for Marfan syndrome. Circulation 74:990-997, 2010.
  9. Faivre L et al. Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation. Eur J Hum Genet. 17:491-501, 2009.
  10. Matyas G et al. Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome. Hum Genet. 122:23-32, 2007.
  11. Loeys BL et al. Aneurysm syndromes caused by mutations in the TGF-Beta receptor N Eng J Med 355(8):788-798, 2006.
  12. Sthenuer C et al. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat 29:E284-E295, 2008.

Forms and Documents

Test Details

FBN1
  • Confirmation of clinical diagnosis in symptomatic patients
  • Risk assessment of asymptomatic family members of a proband with TAAD
  • Differentiation between familial TAAD, Marfan syndrome, Loeys-Dietz syndrome and phenotypically related disorders
  • Exon Array CGH
  • Next-Gen Sequencing

Ordering

918
4 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Buccal Swabs

Billing

81408x1, 81479x1
Yes
Yes
  • 441.9 Aortic aneurysm of unspecified site without mention of rupture Aneurysm Dilatation of aorta, Hyaline necrosis of aorta
  • 441.5 Aortic aneurysm of unspecified site, ruptured Rupture of aorta NOS
  • 759.82 Marfan syndrome
  • 759.7 Multiple congenital anomalies, so described Congenital: anomaly, multiple NOS deformity, multiple NOS
  • 512.8 Other spontaneous pneumothorax Pneumothorax
  • 754.81 Pectus excavatum Congenital funnel chest
  • 737.43 Scoliosis
  • 701.3 Striae atrophicae, Atrophic spots of skin, Atrophoderma maculatum, Atrophy blanche (of Milian), Degenerative colloid atrophy, Senile degenerative atrophy, Striae distensae
  • 379.32 Subluxation of lens
  • 441.00 Unspecified site
* For price inquiries please email zebras@genedx.com

Forms and Documents

Test Details

ACTA2, ADAMTS2, ALDH18A1, ATP6V0A2, ATP7A, B3GALT6, B4GALT7, CBS, CHST14, COL11A1, COL11A2, COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1, COL9A2, DSE, EFEMP2, ELN, FBLN5, FBN1, FBN2, FKBP14, FLNA, LTBP4, MAT2A, MED12, MFAP5, MYH11, MYLK, NOTCH1, PLOD1, PRDM5, PRKG1, PYCR1, RIN2, SKI, SLC2A10, SLC39A13, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR2, ZNF469
  • Molecular confirmation of a clinical diagnosis in symptomatic individuals
  • Risk assessment of asymptomatic family members of a proband diagnosed with a heritable connective tissue disorder
  • Genetic counseling and recurrence risk determination
  • Exon Array CGH
  • Next-Gen Sequencing

Ordering

J555
4 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Buccal Swabs

Billing

81410x1, 81411x1
Yes
Yes
* For price inquiries please email zebras@genedx.com

References

  1. Murphy-Ryan M et al. (2010) Genet Med 12(6):344-54 (PMID: 20467323)
  2. Alazami AM et al. (2016) Hum Genet 135(5):525-40 (PMID: 27023906)
  3. Bradley TJ et al. (2016) Can J Cardiol 32(1):86-99 (PMID: 26724513)
  4. Weerakkody et al. (2016) Genet Med [Epub ahead of print] (PMID: 27011056)
  5. Ziganshin et al. (2015) Ann Thorac Surg 100(5):1604-11 (PMID: 26188975)
  6. Milewicz DM, Regalado E. Thoracic Aortic Aneurysms and Aortic Dissections. 2003 Feb 13 [Updated 2012 Jan 12]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  7. Guo et al. (2015) Am J Hum Genet 96 (1):170-7 (PMID: 25557781)
  8. Barbier et al. (2014) Am J Hum Genet 95(6):736-43 (PMID: 25434006)
  9. Callewaert B et al. Arterial Tortuosity Syndrome. 2014 Nov 13. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  10. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [updated 2013 Jul 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  11. Pepin MG et al. Vascular Ehlers-Danlos Syndrome. 1999 Sep 2 [updated 2015 Nov 19] In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  12. Merla et al. (2012) Circ Cardiovasc Genet 5(6):692-6 (PMID: 23250899)
  13. Beighton P et al. (1998) Am J Med Genet 77(1):31-7 (PMID: 9557891)
  14. Doyle AJ et al. (2012) Nat Genet 44(11):1249-54 (PMID: 23023332)
  15. Sadiq MA, Vanderveen D. (2013) Semin Ophthalmol 28(5-6):313-20 (PMID: 24138040)
  16. Guo et al. (2007) Nat Genet 39(12):1488-93 (PMID: 17994018)
  17. Al-Hussain H et al. (2004) Am J Med Genet 124A(1):28-34 (PMID: 14679583)
  18. Acke FR et al. (2012) Orphanet J Rare Dis 7:84 (PMID: 23110709)
  19. Baumann et al. (2012) Am J Hum Genet 90(2):201-16 (PMID: 22265013)
  20. Chen MH, Walsh CA. FLNA-Related Periventricular Nodular Heterotopia. 2002 Oct 8 [updated 2015 Sep 17]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  21. Greally MT. Shprintzen-Goldberg Syndrome. 2006 Jan 13 [updated 2013 Jun 13]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  22. Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15 [updated 2014 Nov 13]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-201

CREATE A CUSTOM PANEL

Test Details

  • Confirmation of clinical diagnosis in symptomatic patients
  • Genetic counseling and risk assessment of asymptomatic family members of a proband with a hereditary cardiovascular condition

Customizable Cardiology Panel

  • Next-Gen Sequencing
  • Exon Array CGH

Ordering

J779
4 weeks

Billing

Varies by gene
No
Yes
* For price inquiries please email zebras@genedx.com

Forms and Documents

CREATE A CUSTOM PANEL

Test Details

  • Molecular confirmation of a clinical diagnosis in symptomatic individuals
  • Risk assessment of asymptomatic family members of a proband diagnosed with a heritable connective tissue disorder
  • Genetic counseling and recurrence risk determination

Customizable Cardiology Panel

  • ExonArray CGH
  • Next-Gen Sequencing

Ordering

J555C
4 weeks
2-5 mL Blood - Lavender Top Tube
Oral Rinse (30-40 mL)|Buccal Swabs

Billing

81410x1, 81411x1
No
Yes
* For price inquiries please email zebras@genedx.com

References

  1. Murphy-Ryan M et al. (2010) Genet Med 12(6):344-54 (PMID: 20467323)
  2. Alazami AM et al. (2016) Hum Genet 135(5):525-40 (PMID: 27023906)
  3. Bradley TJ et al. (2016) Can J Cardiol 32(1):86-99 (PMID: 26724513)
  4. Weerakkody et al. (2016) Genet Med [Epub ahead of print] (PMID: 27011056)
  5. Ziganshin et al. (2015) Ann Thorac Surg 100(5):1604-11 (PMID: 26188975)
  6. Milewicz DM, Regalado E. Thoracic Aortic Aneurysms and Aortic Dissections. 2003 Feb 13 [Updated 2012 Jan 12]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  7. Guo et al. (2015) Am J Hum Genet 96 (1):170-7 (PMID: 25557781)
  8. Barbier et al. (2014) Am J Hum Genet 95(6):736-43 (PMID: 25434006)
  9. Callewaert B et al. Arterial Tortuosity Syndrome. 2014 Nov 13. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  10. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [updated 2013 Jul 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  11. Pepin MG et al. Vascular Ehlers-Danlos Syndrome. 1999 Sep 2 [updated 2015 Nov 19] In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  12. Merla et al. (2012) Circ Cardiovasc Genet 5(6):692-6 (PMID: 23250899)
  13. Beighton P et al. (1998) Am J Med Genet 77(1):31-7 (PMID: 9557891)
  14. Doyle AJ et al. (2012) Nat Genet 44(11):1249-54 (PMID: 23023332)
  15. Sadiq MA, Vanderveen D. (2013) Semin Ophthalmol 28(5-6):313-20 (PMID: 24138040)
  16. Guo et al. (2007) Nat Genet 39(12):1488-93 (PMID: 17994018)
  17. Al-Hussain H et al. (2004) Am J Med Genet 124A(1):28-34 (PMID: 14679583)
  18. Acke FR et al. (2012) Orphanet J Rare Dis 7:84 (PMID: 23110709)
  19. Baumann et al. (2012) Am J Hum Genet 90(2):201-16 (PMID: 22265013)
  20. Chen MH, Walsh CA. FLNA-Related Periventricular Nodular Heterotopia. 2002 Oct 8 [updated 2015 Sep 17]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  21. Greally MT. Shprintzen-Goldberg Syndrome. 2006 Jan 13 [updated 2013 Jun 13]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  22. Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15 [updated 2014 Nov 13]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-201