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Investigating Racial Differences and Genotype-Phenotype Variation in Marfan Syndrome: A Retrospective Analysis of Genetic and Clinical Features

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical-Adult
  • Secondary Categories:
    • Clinical-Adult & Pediatric
Introduction:
Introduction: Marfan syndrome (MFS) is a connective tissue disorder caused by autosomal dominant variants in the FBN1 gene (either haploinsufficiency (HI) or dominant negative (DN) effects). MFS occurs in ~1 in 10-15,000 individuals and manifests in the ocular, skeletal and cardiovascular systems with variable expressivity. The diagnosis of MFS incorporates clinical features +/- FBN1 genotype using the 2010 Ghent criteria. There is some suggestion in the literature that FBN1 variant type or sex influences vascular phenotype including that patients with HI variants are at increased risk for aortic dissection compared with patients with a DN variants  and males have more frequent aortic root surgeries and aortic dissections. Conversely, ectopia lentis has been associated with DN variants.

Methods:
Methods: Four hundred twenty-nine adult patients (18-82 years) with MFS were investigated to determine whether race, variant type or gender had significant impacts on presentation or vascular outcomes. All patients were seen at the Johns Hopkins Hospital between 2014-2022 and have a diagnosis of MFS according to the 2010 Ghent criteria. Clinical features and outcomes that were assessed included aortic root surgery, presence of type A or B dissection, ectopia lentis (ECL) and pneumothorax.

Results:
Results: 83% of the cohort identified as White, 9% Black and 4% Asian. This does not accurately reflect the racial demographics of the Baltimore-Washington metropolitan area (~50% White, ~25% Black, ~10% Asian). The basis for these disparities is unknown, but may reflect patient access or preferences or referral practices. Many patients travel from out of state which may impose biases regarding knowledge and personal resources. 



Vascular outcomes were not statistically different between racial groups. This included aortic root surgery (White: 37% w/ mean age of surgery – 33yo;   Black: 36% – 26yo; Asian 26% – 29yo);  type A dissection (White: 7%; Black 3%; Asian 5%); and type B dissection (White 7%; Black 13%; Asian 11%). Our cohort had 207 DN variants and 101 HI variants. The vascular outcomes were remarkably similar between HI and DN variant types, with root surgery being the most common event in both groups (~40%), followed by type B (~10%) and type A (~9%) dissections. In keeping with prior published studies, aortic root surgery was more common in males compared to females (48% vs 25%; p-value=0.0000) as was type A dissection (8% of males vs. 5% of females; p-value=0.048).  Type B dissection occurred in 7% of males and 9% of females.



The incidence of pneumothorax or lens subluxation was not significantly different between those with DN vs. HI mutations. Individuals with HI had a slightly higher rate of pneumothorax (14% vs 8%), while those with DN mutations had a slightly higher rate of lens subluxation (37 % vs 28%).  Asians showed a higher incidence of pneumothorax (32%) when compared to Blacks or Whites (15% or 8%, respectively); p=0.0024. ECL was highest in black (54%) when compared to Whites (40%) or Asians (16%); p=0.02). The incidence of neither pneumothorax nor ECL was significantly influenced by sex.

Conclusion:
Conclusion: There are apparent biases in patient access to and representation in our specialized Vascular Connective Tissue Disorder Clinic that caters to all age groups and has a wide referral base. Once seen, patients with MFS of different races had similar vascular outcomes, but men had more type A dissections and root surgery than females. Race but not sex appeared to influence the predisposition for ECL and pneumothorax.

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