At least 20% of cases of syndromic thoracic aortic aneurysm are familial, and at least a dozen genes are implicated. Identifying causative mutations in the diagnostic workup may optimize treatment, according to two presentations at the American Society of Human Genetics (ASHG) 62nd Annual Meeting.
"Marfan syndrome is a connective [tissue] disorder caused by a mutation in fibrillin 1 (FBN1), an extracellular matrix protein. The mutation causes high TGF-β [transforming growth factor beta] signalling in tissues," said Alexander Doyle, a researcher at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, in the session's first talk. TGF-β binds fibrillin 1.
Among the classic symptoms of Marfan syndrome (MFS), which include great height and long limbs and digits, is aortic aneurysm. MFS is autosomal dominant and arises de novo in one third of cases.
Symptoms of the three types of Loeys-Dietz syndrome (LDS), also autosomal dominant, overlap the Marfan phenotype. These include arterial tortuosity, hypertelorism, club feet, bifid or broad uvula, and aneurysms.
"Loeys-Dietz has a striking face and aggressive aneurysm and is caused by mutations in the two TGF-β receptors (1 and 2) and SMAD3," Doyle explained. The effect is to increase TGF-β signalling, which is associated with a broad list of aneurysmal disease and vasculopathies, he added.
The types of mutations that cause LDS, however, suggest a puzzling loss of function of the receptor that underlies the increased signalling. A related disorder, Shprintzen-Goldberg syndrome (SGS), may explain the apparent paradox. SGS, in which craniosynostosis is predominant, also causes all MFS and LDS symptoms as well as skeletal muscle hypoplasia and intellectual disability.
Doyle and his colleagues sequenced the exomes of an affected child and the parents, finding a de novo mutation in the proto-oncogene SKI. The researchers then confirmed the mutation in nine additional sporadic cases. The wild type gene product is a repressor of TGF-β.
Investigation of SKI's altered activity in dermal fibroblasts from patients revealed that the mutation lifts the repression, causing overexpression of TGF-β. This mechanism is consistent with that of MFS. Silencing of SKI in zebrafish recapitulated the phenotype of the human syndrome.
What Signalling Defects Underlie These Related Conditions?
The precise signalling defects underlying these related conditions are not completely understood. "We studied the aortic walls of Loey-Dietz and Marfan patients and saw signatures of increased collagen production along with elastic fiber fragmentation. We saw decrease in TGF-β2 and unexpected increase in TGF-β1," Bart Loeys, MD, another study presenter and professor in the Institute of Genetic Medicine at the University of Antwerp, in Belgium, told attendees. "We hypothesize that a shift in the roles of different cytokines in the TGF-β family is underlying the pathogenesis of these conditions," he continued. Perhaps compensatory paracrine or autocrine events in response to dampened TGF-β signalling lead to "functional overshoot," Dr. Loeys suggested.
To help physicians distinguish these clinically overlapping conditions, the researchers, mostly from Johns Hopkins and the University of Antwerp, are developing a test panel for 12 genes. "It is difficult to predict the genotype from the phenotype, so there is a role for next-generation DNA sequencing for the aortic aneurysm genes within these pathways," Dr. Loey said.
The test panel utilizes HaloPlex technology from Agilent Technologies, which enriches for selected parts of the genome. The panel includes the genes ACTA2, COL3A1, FBLN4, FBN1, FLNA, MYH11, MYLK, NOTCH1, SMAD3, TGF-βR1, TGF-βR2, and SLC2A10. Test panels for up to ten genes are already commercially available.
Treatment for the spectrum of disorders includes beta-blockers, orthopedic surgery, surgery to replace a weakened aortic root, and the drug losartan, an angiotensin II receptor blocker that inhibits TGF-β signalling, which is currently in clinical trials. Harry Dietz, MD, of Johns Hopkins, discovered the Marfan gene and led the team that discovered the repurposing of losartan to treat the disease in 2006. Dr. Dietz and Dr. Loeys discovered and described the syndrome that takes their name in 2005.
The researchers have disclosed no relevant financial relationships.
American Society of Human Genetics (ASHG) 62nd Annual Meeting. Abstracts 70 and 80 and poster 1617T. Presented November 7, 2012.