Genotype-phenotype correlations of marfan syndrome and related fibrillinopathies: Phenomenon and molecular relevance

Abstract

Marfan syndrome (MFS, OMIM: 154700) is a heritable multisystemic disease characterized by a wide range of clinical manifestations. The underlying molecular defect is caused by variants in the FBN1. Meanwhile, FBN1 variants are also detected in a spectrum of connective tissue disorders collectively termed as ‘type I fibrillinopathies’. A multitude of FBN1 variants is reported and most of them are unique in each pedigree. Although MFS is being considered a monogenic disorder, it is speculated that the allelic heterogeneity of FBN1 variants contributes to various manifestations, distinct prognoses, and differential responses to the therapies in affected patients. Significant progress in the genotype–phenotype correlations of MFS have emerged in the last 20 years, though, some of the associations were still in debate. This review aims to update the recent advances in the genotype-phenotype correlations of MFS and related fibrillinopathies. The molecular bases and pathological mechanisms are summarized for better support of the observed correlations. Other factors contributing to the phenotype heterogeneity and future research directions were also discussed. Dissecting the genotype-phenotype correlation of FBN1 variants and related disorders will provide valuable information in risk stratification, prognosis, and choice of therapy.

A novel de novo intragenic duplication in FBN1 associated with early‐onset Marfan syndrome in a 16‐month‐old: A case report and review of the literature

“…FBN1 gene variants lead to disruption in protein production and manifestations of MFS by two primary mechanisms: first, a dominant‐negative effect (primarily in missense and in‐frame variants), in which defective FBN1 monomers impair polymerization and result in weakened, dysfunctional microfibrils. The second mechanism, haplotype insufficiency (more commonly observed in frameshift, nonsense, and splicing variants), causes defective mRNA production and degradation through the nonsense‐mediated mRNA decay system (Chen et al, 2022). Only 1.66% of reported FBN1 pathogenic variants are large rearrangements, of which, 94.1% (48/51) are deletions (Collod‐Béroud et al, 2003; Du et al, 2021).…”

“…The proposita met criteria for MFS based on the Revised Ghent Nosology due to aortic root dilation ( Z ≥ 2) plus a systemic features score ≥7 (aortic root dilation Z ‐score + 8; systemic score of 9) (Loeys et al, 2010). Her FBN1 variant lies within the region of the FBN1 gene that has long been associated with earlier onset symptoms and increased severity of cardiac and phenotypic manifestations of MFS (Chen et al, 2022; Meester et al, 2022; Putnam et al, 1996). According to the UMD‐FBN1 database, two other large duplications in FBN1 have been reported to date.…”

“…Large rearrangements of FBN1 , particularly those resulting in haploinsufficiency, have been associated with a severe MFS phenotype (Chen et al, 2022; Li et al, 2017). Conventional Sanger sequencing, polymerase chain reaction, and molecular analysis fail to detect FBN1 mutations in up to 10% of cases of MFS (Mátyás et al, 2007).…”

Clinical and genetic screening in a large Iranian family with Marfan syndrome: A case study

“…One of the most reliable and enduring associations between genotype and phenotype occurs when the mutation disrupts the cysteine residue, resulting in ectopia lentis. MFS patients with mutations that cause premature termination of translation are more prone to skeletal abnormalities, while ectopia lentis is less common 7 . Extracellular microfibrils, which are essential tissues components that endure repeated stretching and recoil, are primarily composed of FBN1.…”

“…MFS patients with mutations that cause premature termination of translation are more prone to skeletal abnormalities, while ectopia lentis is less common. 7 Extracellular microfibrils, which are essential tissues components that endure repeated stretching and recoil, are primarily composed of FBN1. This protein is present in both elastic and nonelastic connective tissues throughout the body and is often closely associated with elastin fibers.…”