Marfan Syndrome and Related Aortopathies Panel (Exome)

This panel tests for syndromic and non-syndromic causes of thoracic aortic aneurysm and dissection (TAAD). TAAD is a life-threatening disease affecting the aorta and is the 15th leading cause of death in the United States (Hoyert et al. 2001. PubMed ID: 11591077). Aortic dissections most commonly originate in the ascending aorta above the aortic valve (Stanford type A), but can also occur in the descending aorta (Stanford type B). Aneurysms in the cerebral and peripheral artery and abdominal aorta have also been observed (Milewicz and Regalado. 2017. PubMed ID: 20301299). An intense sharp pain in the chest is the most common symptom of aortic dissection. Familial TAAD is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta using imaging studies (MRI, echocardiography, CT), the absence of syndromic conditions that have clinical features that overlap with familial TAAD, and a positive family history. Syndromic forms of TAAD include Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, Shprintzen-Golberg syndrome, congenital contractural arachnodactyly, aneurysms-osteoarthritis syndrome, multisystemic smooth muscle dysfunction syndrome, Ehlers-Danlos syndrome (vascular type, classic type, and kyphoscoliosis form), and periventricular nodular heterotopia.

Lujan syndrome, homocystinuria, Snyder-Robinson syndrome, Meester-Loeys syndrome, and X-linked intellectual disability Hackman-Di Donato type have phenotypic overlap with Marfan syndrome. Patients with Lujan syndrome have cognitive impairment, marfanoid habitus, and craniofacial dysmorphisms (Schwartz et al. 2007. PubMed ID: 17369503). Classic homocystinuria symptoms include developmental delay or intellectual disability, ectopia lentis with or without severe myopia, skeletal abnormalities, osteoporosis, and vascular disease, including potentially fatal thromboembolisms (Sacharow et al. 2017. PubMed ID:20301697; Mudd et al. 2014). Snyder-Robinson syndrome is characterized by mild to moderate X-linked intellectual disability, seizures, speech and gait abnormalities, marfanoid habitus, hypotonia, movement disorders, skeletal changes caused by osteoporosis, and facial dysmorphism (Schwartz et al. 1993. PubMed ID: 23805436). Meester-Loeys syndrome is characterized by X-linked early-onset aortic aneurysm and dissection, joint hypermobility, and other skeletal abnormalities (Meester et al. 2017. PubMed ID: 27632686). X-linked intellectual disability Hackman-Di Donato type is characterized by global developmental delay and marfanoid habitus (Fiordaliso et al. 2019. PubMed ID: 31587868).

Supravalvular aortic stenosis is a congenital narrowing of the ascending aorta. The narrowing of the aorta can lead to shortness of breath, chest pain, and heart failure. Supravalvular aortic stenosis can occur as an isolated condition or as one feature of Williams-Beuren syndrome (Metcalfe et al. 2000. PubMed ID: 11175284).

Cutis laxa is characterized by loose, sagging skin. Occasionally, aortic aneurysms and obstructive pulmonary disease are present (Callewaert et al. 2011. PubMed ID: 21309044).

Aortic imaging is recommended in first degree relatives of individuals with TAAD. Age of onset is highly variable and may occur as early as the perinatal stage to 60-70 years of age (Veiga-Fernández et al. 2020. PubMed ID: 30652519; Hagan et al. 2000. PubMed ID: 10685714).

Advantages of genetic testing for Marfan syndrome and related aortopathies include confirmation of diagnosis, identification of other health risks associated with TAAD, targeted testing of other family members, and assistance with reproductive planning. An early diagnosis of TAAD followed by prophylactic surgical repair and early medical treatment has been demonstrated to reduce the mortality rate (Mody et al. 2014. PubMed ID: 25336626).

Marfan syndrome and related aortopathies may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner, or may arise de novo. Marfan syndrome, Loeys-Dietz syndrome, congenital contractural arachnodactyly, Shprintzen-Golberg syndrome, the vascular and classic types of Ehlers-Danlos syndrome, aneurysms-osteoarthritis syndrome, multisystemic smooth muscle dysfunction syndrome, supravalvar aortic stenosis, cutis laxa, and familial TAAD are inherited in an autosomal dominant manner due to pathogenic variants in the ACTA2, AEBP1, COL3A1, COL5A1, COL5A2, ELN, FBLN5, FBN1, FBN2, FOXE3, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SKI, SMAD2, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, and TGFBR2 genes. Arterial tortuosity syndrome, cutis laxa, homocystinuria, and Ehlers-Danlos syndrome type VI are inherited in an autosomal recessive manner due to pathogenic variants in CBS, EFEMP2, FBLN5, LTBP3, PLOD1, and SLC2A10. X-linked inheritance is observed in FG syndrome, Lujan syndrome, Snyder Robinson syndrome, X-linked intellectual disability Hackman-Di Donato type, and Meester-Loeys syndrome, caused by pathogenic variants in the BGN, FLNA, MED12, NKAP, and SMS genes. Pathogenic missense, nonsense, frameshift, and splicing variants as well as CNV events have been reported in genes associated with Marfan syndrome and related aortopathies (Dietz et al. 2017. PubMed ID: 20301510; Milewicz et al. 2017. PubMed ID: 20301299). 

Pathogenic variants that are associated with TAAD are largely found in genes involved in TGF-β pathway, extracellular matrix and collagen homeostasis, and smooth muscle cell contractile apparatus (Chou and Lindsay. 2020. PubMed ID: 32034893).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

This test is predicted to detect a disease-causing variant in approximately 30% of individuals with familial TAAD (Milewicz and Regalado 2017. PubMed ID: 20301299). FBN1 pathogenic variants have been identified in up to 90% of patients with a clinical diagnosis of Marfan syndrome based on the Ghent nosology (Dietz. 2017. PubMed ID: 20301510; Mátyás et al. 2007. PubMed ID: 17492313). FBN2 pathogenic variants have been identified in up to 75% of individuals diagnosed with congenital contractural arachnodactyly (Nishimura et al. 2007. PubMed ID: 17345643).

More than 95% of patients with clinical findings consistent with Loeys-Dietz have a pathogenic variant in TGFBR1 or TGFBR2 (Loeys and Dietz. 2013. PubMed ID: 20301312).

COL3A1 pathogenic variants have been identified in approximately 95% of individuals with Ehlers-Danlos syndrome (EDS) IV (Pepin and Byers. 2011. PubMed ID: 20301667). COL5A1 and COL5A2 pathogenic variants have been identified in at least 50% of affected individuals with classic EDS (Malfait et al. 2018. PubMed ID: 20301422). Nine out of 12 individuals with EDS type VIA were found to have a pathogenic variant in PLOD1 (Rohrbach et al. 2011. PubMed ID: 21699693).

Twenty-eight out of 29 individuals with Shprintzen-Goldberg syndrome were found to have a pathogenic variant in SKI (Carmignac et al. 2012. PubMed ID: 23103230; Doyle et al. 2012. PubMed ID: 23023332).

95-98% of patients with homocystinuria are found to harbor two pathogenic variants in CBS (Gaustadnes et al. 2002. PubMed ID: 12124992; Kruger et al. 2003. PubMed ID: 14635102; Cozar et al. 2011. PubMed ID: 21520339; Karaca et al. 2014. PubMed ID: 24211323).

This test is predicted to detect pathogenic variants in 22%-35% of supravalvar aortic stenosis patients who do not have gross deletions in the ELN gene (Metcalfe et al. 2000. PubMed ID: 11175284; Micale et al. 2010. PubMed ID: 19844261). 

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.7% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom panels).