Aortopathy Panel, Sequencing and Deletion/Duplication

  • Preferred panel for individuals with 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. 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. 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.

Genetics

Genes

See the Genes Tested table for genes included in the panel.

Prevalence

  • MFS: 1/5,000-10,000
  • Homocystinuria due to cystathionine beta-synthase deficiency (HCY): 1/1,800-335,000
  • EDS, classic type (cEDS, type I/II): 1/20,000
  • EDS, vascular type (vEDS, type IV): at least 1/200,000
  • Thoracic aortic aneurysm and dissection (TAAD): 9-16/100,000 individuals/year; is familial in approximately 20% of cases

Inheritance

  • Commonly autosomal dominant
  • Autosomal recessive for CBS, EFEMP2, PLOD1, and SLC2A10
  • X-linked for BGN and FLNA

Penetrance

  • Complete penetrance is seen in MFS, vEDS, PLOD1-related kyphoscoliotic EDS (kEDS), congenital contractural arachnodactyly (CCA), and Loeys-Dietz syndrome (LDS), with rare exceptions.
  • Reduced penetrance is seen in TAAD and cEDS.

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Analytic Sensitivity

For massively parallel sequencing:

Variant Class Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region Analytic Specificity (NPA)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [Single exon]

>99.9

Exon-levelc duplications

83.3 (56.4-96.4) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

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

Limitations

  • A negative result does not exclude a heritable aortopathy disorder.
  • 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 and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in TGFB3
    • The following regions are not sequenced due to technical limitations of the assay:
      • CBS (NM_001321072) exon(s) 1
      • COL5A1 (NM_000093) exon(s) 1
      • COL5A1 (NM_001278074) exon(s) 1
      • FOXE3 (NM_012186) partial exon(s) 1(Chr1:47882098-47882163)
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by MPS
    • Large duplications less than three exons in size
    • Noncoding transcripts
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single-exon deletions/duplication in the following exons:
    • Gene Exon(s)

      CBS

      (NM_001321072) 1

      COL1A2

      (NM_000089) 3

      COL5A1

      (NM_000093) 1

      COL5A1

      (NM_001278074) 1

      MYLK

      (NM_053025) 13

      MYLK

      (NM_001321309) 12

      MYLK

      (NM_053026) 12

      MYLK

      (NM_053027) 13

      MYLK

      (NM_053028) 12

      NOTCH1

      (NM_017617) 1

Genes Tested

Gene MIM # Associated Disorder(s) Inheritance

ACTA2

102620

Aortic aneurysm, familial thoracic 6

Multisystemic smooth muscle dysfunction syndrome

AD

BGN 301870 Meester-Loeys syndrome XL

CBS

613381

Homocystinuria due to cystathionine beta-synthase deficiency (B6-responsive and nonresponsive types)

Thrombosis (hyperhomocysteinemic)

AR

COL1A1 120150

Combined osteogenesis imperfecta and EDS 1

EDS arthrochalasia type, 1
AD
COL1A2 120160

Combined osteogenesis imperfecta and EDS 2

EDS arthrochalasia type 2
AD
EDS cardiac valvular type AR

COL3A1

120180

EDS, vascular type, type IV

AD

Polymicrogyria with or without vascular-type EDS AR

COL5A1

120215

EDS classic type 1

Multifocal fibromuscular dysplasia

AD

COL5A2

120190

EDS classic type 2

AD

EFEMP2

604633

Cutis laxa, autosomal recessive, type IB

AR

FBN1

134797

MFS

Familial ectopia lentis

MASS syndrome

Marfan lipodystrophy syndrome

AD

FBN2

612570

Congenital contractural arachnodactyly (Beals syndrome)

AD

FLNA

300017

Cardiac valvular dysplasia

Periventricular nodular heterotopia 1

XL

FOXE3 601094 Aortic aneurysm, familial thoracic 11 AD

LOX

153455

Aortic aneurysm, familial thoracic 10

AD

MFAP5 601103 Aortic aneurysm, familial thoracic 9 AD

MYH11

160745

Aortic aneurysm, familial thoracic 4

AD

MYLK

600922

Aortic aneurysm, familial thoracic 7

AD

NOTCH1 190198

Aortic valve disease

Adams-Oliver syndrome 5

AD

PLOD1

153454

EDS kyphoscoliotic type VI

AR

PRKG1

176894

Aortic aneurysm, familial thoracic 8

AD

SKI

164780

Shprintzen-Goldberg craniosynostosis syndrome

AD

SLC2A10

606145

Arterial tortuosity syndrome

AR

SMAD2 601366 LDS 6 AD

SMAD3

603109

LDS 3

AD

SMAD4

600993

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Myhre syndrome

AD

TGFB2

190220

LDS 4

AD

TGFB3

190230

LDS 5

AD

TGFBR1

190181

LDS 1

AD

TGFBR2

190182

LDS 2

AD

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked

Additional Resources