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 |
GeneReviews - Marfan Syndrome
Dietz H. Marfan syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last update: Oct 2017; Accessed: Feb 2020]
GeneReviews - Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency
Sacharow SJ, Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: May 2017; Accessed: Feb 2020]
GeneReviews - Classic Ehlers-Danlos Syndrome
Malfait F, Wenstrup R, De Paepe A. Classic Ehlers-Danlos Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Jul 2018; Accessed: Feb 2020]
GeneReviews - Vascular Ehlers-Danlos Syndrome
Byers PH. Vascular Ehlers-Danlos Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Feb 2019; Accessed: Feb 2020]
GeneReviews - Heritable Thoracic Aortic Disease
Milewicz DM, Regalado E. Heritable Thoracic Aortic Disease Overview. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Revision: Dec 2017; Accessed: Feb 2020]