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Condition report · Musculoskeletal

Marfan Syndrome

Whole genome sequencing identifies the specific FBN1 variant, enabling aortic surveillance protocols and medical management tailored to your genetic profile.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A group of inherited connective tissue disorders that phenotypically resemble Marfan Syndrome, presenting with characteristic features in the skeletal, cardiovascular, and ocular systems, but are caused by distinct genetic mutations.

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in FBN1, which encodes fibrillin-1, a critical structural component of extracellular microfibrils that maintain mechanical integrity and regulate TGF-β signaling. Pathogenic FBN1 variants disrupt microfibril formation, leading to skeletal abnormalities (tall stature, arachnodactyly, pectus deformity, scoliosis), ocular complications (ectopia lentis, myopia, retinal detachment), and the life-threatening cardiovascular manifestations that define the syndrome's natural history.

Marfan syndrome affects approximately 1 in 5,000 to 1 in 10,000 individuals with no ancestral bias. Over 3,800 distinct FBN1 variants have been catalogued. Approximately 90-95% of individuals meeting revised Ghent diagnostic criteria carry a pathogenic FBN1 variant, while 5-10% remain genetically unresolved, likely due to regulatory mutations or deep intronic variants that standard sequencing approaches miss. Approximately 25% of Marfan cases are de novo mutations. Genotype-phenotype correlation is meaningful: haploinsufficiency variants (producing reduced but functional fibrillin-1) typically cause milder aortic disease, while dominant-negative variants (poisoning the microfibril matrix) cause more severe, early-onset aortic progression.

Progressive aortic root dilatation is the primary driver of morbidity and mortality in Marfan syndrome. Prior to modern medical management, sudden aortic dissection was the leading cause of death in the third to fourth decade of life. A confirmed FBN1 pathogenic variant mandates lifelong cardiovascular surveillance via echocardiography to monitor aortic root diameter; prophylactic aortic root surgery is indicated at 5.0 cm (or 4.5 cm with family history of dissection). Beta-blockers and ARBs slow aortic dilatation by reducing dP/dt and blunting TGF-β signaling. Genetic diagnosis enables cascade screening of first-degree relatives (approximately 50% carry the familial variant), identifying presymptomatic carriers who benefit from surveillance before aortic disease progresses to dissection risk.

FBN1 variant type predicts clinical course: haploinsufficiency variants typically cause milder disease, while dominant-negative variants drive aggressive early-onset aortic dilatation requiring intensive surveillance.

The 6 conditions we analyse

Congenital Contractural Arachnodactyly

Autosomal dominant

Congenital contractural arachnodactyly (CCA, Beals syndrome) is a connective tissue disorder characterized by multiple flexion contractures, arachnodactyly, severe kyphoscoliosis, abnormal pinnae and muscular hypoplasia.

Genes analysed

Also known as

arachnodactyly, contractural Beals type; distal arthrogryposis type 9; Beals syndrome; Beals-Hecht syndrome; CCA; CCA syndrome; contractures, multiple with arachnodactyly; DA9; Ear anomalies-contractures-dysplasia of bone with kyphoscoliosis

MONDO:0007363OMIM 121050Orphanet 115MedGen 67391

Loeys-Dietz Syndrome

Autosomal dominant

Loeys-Dietz syndrome is a rare genetic connective tissue disorder characterized by a broad spectrum of craniofacial, vascular and skeletal manifestations with five genetic subtypes described forming a clinical continuum.

Genes analysed

Also known as

aortic aneurysm syndrome due to TGF-beta receptors anomalies; aortic aneurysm syndrome, Loeys-Dietz type

Includes 6 related subtypes ↓
  • aneurysm-osteoarthritis syndrome
  • Loeys-Dietz syndrome 1
  • Loeys-Dietz syndrome 2
  • Loeys-Dietz syndrome 4
  • Loeys-Dietz syndrome 6
  • Rienhoff syndrome
MONDO:0018954Orphanet 60030MedGen 395827

Shprintzen-Goldberg Syndrome

Autosomal dominant

Shprintzen-Goldberg syndrome (SGS) is a very rare genetic disorder characterized by craniosynostosis, craniofacial and skeletal abnormalities, marfanoid habitus, cardiac anomalies, neurological abnormalities, and intellectual disability.

Genes analysed

Also known as

Marfanoid craniosynostosis syndrome; Marfanoid disorder with craniosynostosis type 1; SGS; Shprintzen-Goldberg craniosynostosis syndrome; Shprintzen-Goldberg marfanoid syndrome

MONDO:0008426OMIM 182212Orphanet 2462MedGen 231160

Marfan Syndrome

Autosomal dominant

A disorder of the connective tissue. Connective tissue provides strength and flexibility to structures throughout the body such as bones, ligaments, muscles, walls of blood vessels, and heart valves. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). It is caused by mutations in the FBN1 gene, which provides instructions for making a protein called fibrillin-1. Marfan syndrome is inherited in an autosomal dominant pattern. At least 25% of cases are due to a new (de novo) mutation. Treatment is based on the signs and symptoms in each person.

Genes analysed

Also known as

Marfan syndrome type 1; Marfan's syndrome; MFS; MFS1

Includes 1 related subtype ↓
  • neonatal Marfan syndrome
MONDO:0007947OMIM 154700Orphanet 284963Orphanet 558MedGen 44287

Meester-Loeys syndrome

X-linked recessive

BGN-related aortic aneurysm and dissection with joint and skeletal features, mainly in males.

Genes analysed

Also known as

MRLS; X-linked severe syndromic TAAD; X-linked severe syndromic thoracic aortic aneurysm and dissection

MONDO:0010515OMIM 300989Orphanet 622925MedGen 934778

Marfanoid-progeroid-lipodystrophy syndrome

Autosomal dominant

Specific FBN1 variants causing a tall, slender build with near-total lack of body fat and an aged appearance.

Genes analysed

Also known as

Marfan lipodystrophy syndrome; MFLS

MONDO:0014831OMIM 616914Orphanet 300382MedGen 934763

Why whole genome sequencing

Standard FBN1 panels miss 5-10% of pathogenic variants. These elude detection because they hide in regulatory regions or deep intronic sequences.

The FBN1 variant causing your aortic risk may not be detected

Although FBN1 is the sole gene associated with Marfan syndrome, targeted panels vary in comprehensiveness. Standard exome-focused sequencing captures most of the coding sequence but frequently misses regulatory region variants, deep intronic changes, and complex rearrangements. Approximately 5-10% of clinically affected individuals meeting revised Ghent criteria have negative molecular testing, not because a variant isn't present, but because standard panels aren't designed to find it. Whole genome sequencing provides complete FBN1 coverage including intronic and regulatory regions, capturing the full spectrum of pathogenic variants.

Knowing your FBN1 variant guides your lifelong surveillance strategy

A confirmed FBN1 pathogenic variant does more than confirm diagnosis; it predicts your aortic disease trajectory. Haploinsufficiency variants typically show slower aortic progression and lower dissection risk; dominant-negative variants show aggressive early-onset dilatation. This genotype-phenotype correlation informs surveillance intensity, beta-blocker dosing, and timing of prophylactic surgery. Approximately 50% of first-degree relatives in your family carry the variant. Cascade genetic screening identifies presymptomatic relatives who can begin surveillance before aortic complications emerge.

Other musculoskeletal conditions

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