Marfan Syndrome and Related Aortopathies Panel (PG-Select)

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 also can 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. 2012. 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, and Snyder-Robinson syndrome have phenotypic overlap with Marfan syndrome. Patients with Lujan syndrome have cognitive impairment and marfanoid habitus, and craniofacial dysmorphisms (Lujan et al. 1984. PubMed ID: 6711603; Schwartz et al. 2007. PubMed ID: 17369503). Classic homocystinuria symptoms include developmental delay or intellectual disability, ectopia lentis and/or severe myopia, skeletal abnormalities, osteoporosis, and vascular disease, including potentially fatal thromboembolisms (Kraus et al. 1999. PubMed ID: 10338090; Picker and Levy. 2014. 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 and movement disorders, skeletal changes caused by osteoporosis, and facial dysmorphism (Cason et al. 2003. PubMed ID: 14508504; Becerra-Solano et al. 2009. PubMed ID: 19206178; Albert et al. 2015. PubMed ID: 25888122).

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 of dilatation is variable within families.

Marfan syndrome, Loeys-Dietz syndrome, congenital contractural arachnodactyly, Shprintzen-Golberg syndrome, aneurysms-osteoarthritis syndrome, multisystemic smooth muscle dysfunction syndrome, supravalvar aortic stenosis, cutis laxa, Ehlers-Danlos vascular and classic type, and familial TAAD are inherited in an autosomal dominant manner due to pathogenic variants in the FBN1, TGFBR1, TGFBR2, TGFB2, TGB3, FBN2, SKI, ELN, FBLN5, COL5A1, COL5A2, COL3A1, MYLK, MYH11, ACTA2, FOXE3, LOX, MAT2A, MFAP5, NOTCH1, PRKG1, SMAD3, and SMAD4 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 SLC2A10, EFEMP2, FBLN5, CBS, and PLOD1, respectively. FG syndrome, Lujan syndrome, and Snyder Robinson syndrome are inherited in an X-linked manner due to FLNA, MED12, and SMS genes.

See individual test descriptions for information on molecular biology of gene products and mutation spectra.

This test is predicted to detect a disease-causing variant in approximately 30% of individuals with familial thoracic aortic aneurysm and dissection (TAAD) (Milewicz and Regalado 2012. 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 2011. 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 (CCA) (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. 2011). 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). FLNA pathogenic variants were identified in 26 out of 41 patients with FLNA-related disorders (OPD1, OPD2, FMD, MNS) (Robertson et al. 2003. PubMed ID: 12612583). 95-98% of patients with homocystinuria are found to harbor two pathogenic variants (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). 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). This test is predicted to detect pathogenic variants in 22%-35% of Supravalvar aortic stenosis patients that do not have gross deletions in the ELN gene (Metcalfe et al. 2000. PubMed ID: 11175284; Micale et al. 2010. PubMed ID: 19844261). Deletions of 7q11.23 which encompasses the ELN gene are commonly found in individuals with Williams syndrome. This NGS test will only detect copy number changes in the ELN gene, therefore we will not be able to determine how many additional genes are deleted in patients with Williams syndrome.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.