Aortopathy Panel, Sequencing and Deletion/Duplication

Aortopathy Panel, Sequencing and Deletion/Duplication 2006540
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
  • Clinical phenotype of aortic or vascular aneurysm, dissection, or rupture if no single specific diagnosis is strongly suspected
  • If an individual meets clinical criteria for a specific disorder or if a specific diagnosis is suspected, consider more targeted gene testing first (see Related Tests).

Aortopathy disorders are characterized by progressive aortic dilation, dissection, and other vascular findings, and may involve multiple organ systems. If an individual meets clinical criteria for a specific disorder (eg, Marfan syndrome [MFS], Ehlers-Danlos syndrome[EDS]) or if a specific diagnosis is suspected, consider more targeted gene testing first.

Disease Overview

Symptoms

  • Aneurysm, dissection, and/or rupture of the aorta in any aortic section, including the aortic root or arch, ascending or descending aorta
  • Cerebral, thoracic, and abdominal arterial aneurysms and/or dissections
  • Skeletal manifestations, joint laxity, or craniofacial features

Etiology

Pathogenic variants in genes associated with aortopathy lead to structurally weakened cardiac, vascular, and/or connective tissues that become prone to progressive aneurysm, dissection, and/or rupture. Malformations of the heart, dysmorphic features, joint and skin laxity, and skeletal defects may also occur.

Prevalence

  • MFS – 1/5,000-10,000
  • Homocystinuria due to cystathionine beta-synthase deficiency (HCY) – 1/1,800-800,000
  • EDS, type I/II (EDS I/II) – 1/20,000
  • EDS, type IV (EDS IV) – at least 1/250,000
  • Thoracic aortic aneurysm and dissection (TAAD) – 9 to 16/100,000 individuals/year; is familial in approximately 20 percent of cases

Inheritance

  • Autosomal recessive for CBS, EFEMP2, PLOD1, and SLC2A10
  • X-linked for FLNA
  • Autosomal dominant for all other genes

Genotype-Phenotype Correlation

  • Clinical phenotype may vary and overlap among disorders.
  • Complete penetrance is seen in MFS, EDS IV, EDS VI, congenital contractoral arachnodactyly (CCA), and Loeys-Dietz syndrome (LDS), with rare exceptions.
  • Reduced penetrance is seen in TAAD and EDS I/ II.
  • May include previously undiagnosed Turner syndrome.

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Indications for Ordering

  • Clinical phenotype of aortic or vascular aneurysm, dissection, or rupture if no single specific diagnosis is strongly suspected
  • If an individual meets clinical criteria for a specific disorder or if a specific diagnosis is suspected, consider more targeted gene testing first.

Limitations

  • A negative result does not exclude a heritable form of MFS, HCY, EDS, TAAD, CCA, or LDS.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted gene(s)
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in LOX
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
      • COL3A1 (NM_000090) 6, 7, 9, 13; COL5A1 (NM_000093) 1, 16, 20; COL5A2 (NM_000393) 36; MYH11 (NM_001040113) 42; PRKG1 (.
      • NM_006258) 8, 17; TGFBR1 (NM_004612) 1

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene Alias Symbol(s) MIM Number Disorder Inheritance

ACTA2

ACTSA

102620

Aortic aneurysm, familial thoracic 6

Multisystemic smooth muscle dysfunction syndrome

Moyamoya disease 5

AD

CBS

HIP4

613381

Homocystinuria due to cystathionine beta-synthase deficiency

Vitamin b6-responsive and vitamin b6-nonresponsive types of homocystinuria

Thrombosis

Hyperhomocysteinemic

AR

COL3A1

EDS4A

120180

Ehlers-Danlos syndrome, vascular type, type IV

AD

COL5A1

 

120215

Ehlers-Danlos syndrome, classic types, I/II

AD

COL5A2

 

120190

Ehlers-Danlos syndrome, classic type, I

AD

EFEMP2

FBLN4, UPH1

604633

Cutis laxa, autosomal recessive, type IB

AR

FBN1

FBN, MFS1, WMS, MASS, OCTD, SGS

134797

MFS

Acromicric dysplasia

Ectopia lentis 1, isolated, autosomal dominant

MASS syndrome

Weill-Marchesani syndrome 2

Geleophysic dysplasia 2

Marfan lipodystrophy syndrome

AD

FBN2

CCA, DA9

612570

Beals syndrome, congenital contractural arachnodactyly

Arthrogryposis, distal, type 9

AD

FLNA

FLN1, FLN, OPD2, OPD1, ABP-280

300017

Cardiac valvular dysplasia, x-linked

FG syndrome 2

Frontometaphyseal dysplasia 1

Periventricular nodular heterotopia 1

XL

LOX

 

153455

Aortic aneurysm, familial thoracic 10

AD

MYH11

SMMHC, SMHC

160745

Aortic aneurysm, familial thoracic 4

AD

MYLK

MLCK, smMLCK, MYLK1, MLCK1

600922

Aortic aneurysm, familial thoracic 7

AD

PLOD1

LLH, PLOD, LH1

153454

EDS

Kyphoscoliotic type, VI

AR

PRKG1

PRKGR1B, PRKG1B, PGK, PKG, PKG1

176894

Aortic aneurysm, familial thoracic 8

AD

SKI

 

164780

Shprintzen-Goldberg craniosynostosis syndrome

AD

SLC2A10

GLUT10

606145

Arterial tortuosity syndrome

AR

SMAD3

MADH3, JV15-2, HsT17436

603109

LDS 3

AD

SMAD4

MADH4, DPC4

600993

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Juvenile polyposis syndrome

Myhre syndrome

AD

TGFB2

 

190220

LDS 4

AD

TGFB3

ARVD1, ARVD

190230

LDS 5

Arrhythmogenic right ventricular dysplasia, familial, 1

AD

TGFBR1

MSSE, ESS1, ALK-5, ACVRLK4, ALK5, TBRI, TBR-i

190181

LDS 1, types 1B/2B

Aortic aneurysm, familial thoracic 5

AD

TGFBR2

MFS2, TBRII, TBR-ii

190182

LDS 2, types 1B/2B

AD

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked
References 
  1. Dietz H. Marfan Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2017. Seattle, WA [Last Update: Oct 2017; Accessed: May 2019]
  2. Sacharow S, Picker J, Levy H. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: May 2017; Accessed: Nov 2018]
  3. Malfair F, Wenstrup R, De Paepe A. Classic Ehlers-Danlos Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Jul 2018; Accessed: Nov 2018]
  4. Vascular Ehlers-Danlos Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Nov 2015; Accessed: Nov 2018]
  5. Heritable Thoracic Aortic Disease Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Revision: Dec 2017; Accessed: Nov 2018]

Last Update: April 2019