Gene test interpretation: FBN1 (Marfan syndrome gene)

INTRODUCTION — The FBN1 gene encodes fibrillin-1, an important extracellular matrix protein in elastic and nonelastic tissues. FBN1 is the Marfan syndrome (MFS) gene.

This monograph summarizes interpretation of FBN1 genetic testing. Evaluation and management of MFS are discussed separately [1]. (See 'Resources' below.)

How to read the report — The table summarizes considerations in reviewing genetic test results (table 1). These include obtaining the actual report, confirming the report belongs to the patient, checking the qualifications of the testing laboratory, determining which gene(s) were tested, and reviewing the testing method. The glossary summarizes terms that may be used (table 2). A more extensive glossary is also available. (See "Genetics: Glossary of terms".)

Testing for clinical care should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. If the results are used in clinical decision-making and the original testing was not from a CLIA-certified laboratory, it should be repeated. This applies to positive results and negative results in an individual considered to be at risk.

FBN1 gene — FBN1 was identified as the disease gene for MFS in the early 1990s. Subsequently, hundreds of pathogenic variants in FBN1 have been reported in individuals with MFS [2].

Approximately three-fourths of individuals with MFS have an affected parent who shares the same FBN1 variant; the remaining one-fourth have a de novo mutation and a negative family history. Transmission is autosomal dominant. Sometimes clinical features differ between family members due to age-dependent manifestations, intrafamilial variable expressivity, or mosaicism. (See 'Clinical findings' below and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Mosaicism'.)

FBN1 variants are numerous and scattered throughout the gene. Genetic testing requires next-generation sequencing that includes all coding exons and intron-exon boundaries, either alone or as part of a multigene panel. Genetic testing should include both sequencing and deletion/duplication analysis. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Whole genome, exome, or gene panel'.)

Most FBN1 variants lack genotype-phenotype correlations. Rare exceptions include:

●Variants clustered between exons 24 and 32 can cause an early-onset, severe and rapidly progressive presentation of MFS; however, the severity of manifestations is a continuum, and not all variants in this region cause severe disease.

●A comprehensive clinical evaluation and application of the clinical diagnostic criteria for MFS can often aid in the interpretation of a variant of uncertain significance (VUS) in FBN1. The situation can remain ambiguous in individuals with mild clinical presentations that do not include some of the most specific features of MFS such as ectopia lentis or the characteristic combination of skeletal findings.

●The finding of a pathogenic variant in FBN1 does not establish the diagnosis of MFS; pathogenic variants in FBN1 can also cause other connective tissue disorders or skeletal dysplasias, including stiff skin syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, and acromelic dysplasia. While the pathogenic variants in FBN1 that cause phenotypes distinct from MFS are known to cluster in specific domains of fibrillin-1, pathogenic variants in the same domains can be associated with classic MFS. Therefore, the nature and location of a pathogenic variant in FBN1 are not fully predictive of the phenotypic consequences. (See "Skeletal dysplasias: Specific disorders", section on 'Geleophysic dysplasia' and "Causes of short stature", section on 'Skeletal dysplasias/growth plate abnormalities'.)

Approximately 5 to 10 percent of individuals who meet clinical criteria for MFS lack an identifiable pathogenic variant in FBN1. Some of these individuals have FBN1 variants that are more challenging to detect by conventional testing technologies, such as a deep intronic variant that activates a cryptic splice site. Some may have other syndromes that overlap with MFS associated with other genes. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Genetics'.)

MARFAN SYNDROME

Typical diagnostic approach — MFS is likely underdiagnosed. The classic syndrome is seen in approximately 1 in 5000 to 10,000 individuals, which may underestimate the true prevalence [3].

An FBN1 variant that is formally classified as pathogenic or likely pathogenic is sufficient for diagnosing MFS in most circumstances. There is a specific additional requirement for a minimal set of clinical findings in the proband, a positive family history of MFS, or prior association of the specific variant with MFS that includes aortic root enlargement and/or dissection [4,5]. Such factors are often integrated into allele classification by the laboratory, but this should be documented in the test report. (See 'How to read the report' above.)

Documentation of a pathogenic variant in FBN1 is not required to diagnose MFS; most individuals can be diagnosed based on clinical criteria (the revised Ghent nosology) [6]. Lack of an identifiable pathogenic variant in FBN1 does not exclude the diagnosis of MFS if clinical findings are sufficient to independently meet established diagnostic criteria, although other diagnostic possibilities must also be considered. The differential diagnosis is discussed separately. (See 'FBN1 gene' above and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Differential diagnosis'.)

Critically, lack of identification of a pathogenic variant in FBN1 (or any genes on a multigene panel) does not exclude risk in someone with a personal or family history of aortic root aneurysm, vascular disease, or other connective tissue findings. A negative result should only be used to discontinue clinical follow-up in a given individual if a definitive variant that has been documented in affected relatives has been excluded and the individual under consideration does not have physical or laboratory findings that independently warrant ongoing observation.

Involvement of a genetics professional or expert in MFS and related syndromes is appropriate in any individual (child or adult of any age) in whom these disorders are suspected, as well as in anyone with a pathogenic or likely pathogenic variant in FBN1 or other systemic connective tissue disorder gene, even if symptoms are absent. A delay in diagnosis can be potentially life-threatening due to the risk of aortic rupture. (See 'Locating a genetics expert' below.)

Protection from genetic discrimination is discussed separately. (See "Genetic testing", section on 'Genetic discrimination'.)

Clinical findings — MFS is a disorder of connective tissue with clinical features involving the cardiovascular system, skeleton, eye, and other organ systems (table 3) [6]. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Clinical manifestations of MFS'.)

●Cardiovascular – Aortic root aneurysm (dilation) can be progressive and can cause aortic valve regurgitation or aortic dissection or rupture. Mitral valve prolapse is often associated with mitral regurgitation, which can be progressive and lead to heart failure. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Aortic disease' and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Cardiac disease'.)

●Bones and joints – Overgrowth of long bones can cause taller than expected stature, kyphoscoliosis, and arachnodactyly. Elongation of the ribs can push the sternum anteriorly (pectus carinatum) or posteriorly (pectus excavatum). A high-arched palate can lead to crowding of the teeth. Joint hypermobility can be present, although reduced elbow extension is often noted. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Skeletal findings'.)

●Eye – Ocular changes can include myopia (which can be early in onset and rapidly progressive), dislocation of the lens, glaucoma, flat cornea, and hypoplasia of the iris or ciliary muscles. There is a risk for retinal detachment. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Ocular abnormalities'.)

New or worsening manifestations may occur throughout life [7].

Management considerations — People with MFS and related connective tissue disorders such as Loeys-Dietz syndrome or vascular Ehlers-Danlers syndrome can have potentially life-threatening complications related to aortic dissection or aortic rupture. Complications can occur in children and adults. Branch arteries can also be involved and can be associated with life-threatening complications.

Appropriate management by a geneticist and/or cardiologist with expertise in these syndromes is essential. Often a multidisciplinary team is involved. Resources for locating an expert are listed below. (See 'Resources' below.)

The expert or multidisciplinary team will discuss risks and risk reduction [8]. The summary table (table 3) and information below is only intended to illustrate the range of complex management decisions involved and cannot substitute for the role of these experts (see "Management of Marfan syndrome and related disorders"):

●Cardiovascular – Risks include aortic dissection and rupture. Considerations include the appropriate surveillance strategy, role of medical therapies such as beta blockers or angiotensin receptor blockers, avoidance of certain medications such as fluoroquinolones and calcium channel blockers, and indications for preventive interventions including surgery. Heart valve dysfunction and heart failure can also occur in people with MFS. (See "Management of Marfan syndrome and related disorders", section on 'Aortic monitoring' and "Management of Marfan syndrome and related disorders", section on 'Drug therapy'.)

●Bones and joints – A range of interventions (nonsurgical and surgical) are available for skeletal abnormalities such as scoliosis, pectus excavatum or carinatum, severe flat feet, and high-arched palate with dental abnormalities. (See "Management of Marfan syndrome and related disorders", section on 'Treatment for other complications of MFS'.)

●Sports and activities – The major risk is thought to be associated with activities that increase blood pressure, leading to aortic wall stress. Individuals are advised to avoid weightlifting and other activities that require Valsalva maneuvers, exercising to exhaustion, and contact sports leading to sharp blows to the head or chest or sudden acceleration or deceleration. Patient (and family/caregiver) education and shared decision-making is important to make activity plans that allow for social engagement and good cardiovascular health while avoiding both inactivity and activities that could increase risk of vascular catastrophe. (See "Management of Marfan syndrome and related disorders", section on 'Restriction of strenuous activity'.)

●Pregnancy – Pregnancy is managed as high risk by a multidisciplinary team. Reproductive counseling is important to understand risks of transmission and alternative reproductive options. (See "Heritable thoracic aortic diseases: Pregnancy and postpartum care" and 'Reproductive counseling' below.)

FIRST-DEGREE RELATIVES

Likelihood of carrying the variant — First-degree relatives of an individual with a pathogenic or likely pathogenic variant in FBN1 should be tested for the variant:

●The likelihood of inheriting the variant is 50 percent for children of an individual with an FBN1 variant. Approximately three-fourths of individuals will inherit the variant from a parent. (See 'FBN1 gene' above.)

●Siblings may have up to 50 percent risk depending on whether the variant arose de novo or was inherited. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Autosomal dominant'.)

Reproductive counseling — Pre- or post-conception genetic testing and counseling are appropriate for prospective parents with MFS. The discussion may include the likelihood of an affected child; alternative reproductive options; preconception, pregnancy, and postpartum management; and plans for evaluations and interventions after birth should the child inherit the FBN1 variant. (See "Heritable thoracic aortic diseases: Preconception risk assessment and management", section on 'General preconception care'.)

Children — At-risk children should generally be tested as soon as possible. Certain exceptions may apply, such as in kindreds without significant aortic abnormalities during childhood. Final decisions about testing are made by the family/caregivers with shared decision-making in consultation with a genetics or MFS expert.

RESOURCES

Information on MFS

●The Marfan Foundation website (Marfan.org) provides resources for patients and professionals, including resources for locating an expert [9].

●UpToDate topics:

•Diagnosis – (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

•Management – (See "Management of Marfan syndrome and related disorders".)

•Pregnancy – (See "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

•Athletics – (See "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Marfan syndrome'.)

•Guidelines – (See "Society guideline links: Marfan syndrome".)

Locating a genetics expert

●Genetic counselors – National Society of Genetic Counselors (NSGC)

●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)