Massively Parallel Sequencing
- Preferred panel for individuals with clinical phenotype of aortic or vascular aneurysm, dissection, or rupture if no single specific diagnosis is strongly suspected
- If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information
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, or NGS) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large 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
- Deletions/duplications in TGFB3
- Breakpoints of large deletions/duplications
- SNVs and small deletions/insertions will not be called in the following exons 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 massively parallel sequencing
- 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
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 |