Aortopathy and connective tissue genes

Alport Syndrome, X-linked

Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies [1]. X-linked Alport syndrome is largely caused by mutations in COL4A5 which codes for a component of type IV collagen. Abnormal type IV collagen in glomeruli can prevent the kidneys from adequately filtering the blood and allows blood and protein to pass into the urine, resulting in progressive scarring of kidney tissue [2].

Gene name Transcript Clinical sensitivity
COL4A5 ENST00000328300.6 ~65% [3] 

Elastin-related phenotypes or Cutis laxa

Cutis laxa (CL) is a connective tissue disorder characterised by excessive loose, wrinkled and inelastic skin due to structural defects in the elastic fibres or abnormal maturation and secretion of proteins involved [4]. Syndromic forms of CL include autosomal dominant, autosomal recessive and X-linked modes of inheritance [5]. In autosomal dominant CL, phenotypic variability is common with some patients carrying genetic variants in the ELN or FBLN5 genes [4]. Autosomal recessive CL is the most common form of inherited neonatal CL and may be attributed to mutations in EFEMP2 (FBLN4), FBLN5 and ATP6V0A2 genes [4]

Gene name Transcript Clinical sensitivity
ATP6V0A2 ENST00000330342.3 ~24% [6] 
EFEMP2  ENST00000307998.6 ~13% [7]
ELN  ENST00000358929.4  N/A
FBLN5  ENST00000342058.4 ~17% [8]

Ehlers-Danlos syndrome (EDS)

The Ehlers-Danlos syndromes comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders, which are characterised by joint hypermobility, skin hyperextensibility, and tissue fragility [9]. Mutations in more than a dozen genes have been found to cause Ehlers-Danlos syndrome. The classical type results most often from mutations in either the COL5A1 gene or the COL5A2 gene. Mutations in the TNXB gene have been found in a very small percentage of cases of the hypermobility type (although in most cases, the cause of this type is unknown). The vascular type results from mutations in the COL3A1 gene. PLOD1 gene mutations cause the kyphoscoliosis type. Mutations in the COL1A1 gene or the COL1A2 gene result in the arthrochalasia type. The dermatosparaxis type is caused by mutations in the ADAMTS2 gene. Other, less well-characterised forms of Ehlers-Danlos syndrome result from mutations in additional genes [10].

Gene name Transcript Clinical sensitivity
ADAMTS2 ENST00000251582.7  
B3GALT6 ENST00000379198.2   
B4GALT7  ENST00000029410.5  
CHST14 ENST00000306243.5  
COL1A1  ENST00000225964.5  
COL1A2 ENST00000297268.6  
COL3A1 ENST00000304636.3  
COL5A1  ENST00000371817.3  ~46% [11] 
COL5A2 ENST00000374866.3 ~4% [11]
FKBP14  ENST00000222803.5  
PLOD1  ENST00000196061.4 >90% in EDS kyphoscoliotic type [12]
RIN2  ENST00000255006.6  
SLC39A13 ENST00000362021.4  
TNXB ENST00000375247.2   
ZNF469  ENST00000437464.1   

Familial thoracic aortic aneurysm (FTAA)

FFamilial thoracic aortic aneurysm (FTAA) is more common than previously recognised and has an indolent growth pattern that is silent but lethal. Predicting the risk of rupture or dissection based upon aortic dimension is possible. Once dissection occurs, short- and long-term outcomes are dismal. Up to 20% of thoracic aortic aneurysms are inherited, with heterogeneous genetic factors and variable penetrance [13]Loci for isolated thoracic aortic aneurysm have been identified on chromosomes 11q (AAT1) and 5q (AAT2) and pathogenic variants in the MYH11, ACTA2, MYLK and PRKG1 genes are known causes [13]

Gene name  Transcript Clinical Sensitivity
ACTA2  ENST00000458208.1   
BGN ENST00000331595   
COL3A1 ENST00000304636   
COL5A1 ENST00000371817  
COL5A2 ENST00000374866  
EFEMP2 ENST00000307998  
ELN ENST00000358929.4   
FBN1 ENST00000316623.5   
FBN2 ENST00000262464.4   
FLNA ENST00000369850.3   
FOXE3 ENST00000335071.2  
LOX ENST00000231004.4   
MAT2A ENST00000306434.3   
MFAP5 ENST00000359478.2  
MYH11 ENST00000452625.2   
MYLK ENST00000360304.3   
NOTCH1  ENST00000277541.6   
PLOD1 ENST00000196061   
PRKG1 ENST00000373980.4   
SKI  ENST00000378536.4   
SLC2A10 ENST00000359271  
BGN ENST00000331595.4   
SMAD2  ENST00000359271   
SMAD3 ENST00000327367.4  
SMAD4 ENST00000342988.3  
SMAD6 ENST00000288840  
TGFB2 ENST00000366929.4  
TGFB3 ENST00000238682  
TGFBR1 ENST00000374994.4  
TGFBR2 ENST00000359013.4  

Loeys-Dietz syndrome (LDS)

Loeys-Dietz syndrome (LDS) is an aortic aneurysm syndrome characterised by vascular, skeletal, cutaneous, and craniofacial findings. Affected patients have a high risk of aortic dissection or rupture at an early age.  Intrafamilial clinical variability has been described and rare examples of non-penetrance in LDS have been documented [14]. Pathogenic variants in the TGFBR1, TGFBR2, SMAD3, and TGFB2 genes are known to cause LDS and pathogenic variants are detected in more than 95% of patients with typical LDS [14]. LDS is inherited in an autosomal dominant manner but approximately 75% of probands have a de novo pathogenic variant [14]

Gene name Transcript

Clinical sensitivity

SMAD3  ENST00000327367.4  ~5% [14] 
TGFB2  ENST00000366929.4  ~1% [14] 
TGFB3  ENST00000238682.3 Rare [15
TGFBR1  ENST00000374994.4  ~70% [14]
TGFBR2  ENST00000359013.4 ~20% [14

Marfan syndrome 

Marfan syndrome (MFS) is a systemic disorder of connective tissue with a high degree of clinical variability. The definition of MFS is based on several sets of criteria, the latest being the Ghent II nosology [16]It is considered to be an autosomal dominant disorder associated with a mutation in FBN1 and the typical phenotypical manifestations. The latter involve the ocular, skeletal, and cardiovascular systems. Cardiovascular manifestations include dilatation of the aorta, a predisposition for aortic tear and rupture, mitral and tricuspid valve prolapse and enlargement of the proximal pulmonary artery. These are major sources of morbidity and early mortality. The estimated prevalence of MFS is 1:3,000-1:5,000 [17]. [17]. Although intrafamilial clinical variability can be extensive, clinical penetrance is high [17]. Pathogenic variants in the FBN1 gene are found in ~70%-93% of probands [17]

Gene name Transcript Clinical sensitivity
FBN1 ENST00000316623.5 70-93% [17,18]
FBN2 ENST00000262464.4 ~43% in congenital contractural arachnodactyly [19] 
SMAD3  ENST00000327367.4 n/a 
TGFBR1 ENST00000374994.4 n/a
TGFBR2 ENST00000359013.4 n/a

Weill-Marchesani syndrome 

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, proportionate short stature, brachydactyly, and joint stiffness [20]. WMS is described as being very rare. Prevalence has been estimated at 1:100,000 population [20]. Pathogenic variants in ADAMTS10 are known to cause autosomal recessive WMS, recently a pathogenic variant in LTPBP2 has been reported in one family with autosomal recessive inheritance [20].

Gene name Transcript Clinical sensitivity
ADAMTS10 ENST00000597188.1 n/a - variants identified in the vast majority of patients [21]
ADAMTS17 ENST00000268070.4 n/a
LTBP2 ENST00000261978.4 n/a

Other genes included in the aortopathy and vasculopathy NGS panel

Gene name  Disease Transcript
ABCC6 Homocystinuria, Thrombosis, hyperhomocysteinemic ENST00000205557.7
ACVR1 (ALK1) Abdominal aortic aneurysm ENST00000263640.3
ADAMTSL2 Abdominal aortic aneurysm ENST00000354484.4
ADAMTSL4 Abdominal aortic aneurysm ENST00000369039.5
CBS Abdominal aortic aneurysm ENST00000398165.3
CNTN3 Abdominal aortic aneurysm ENST00000263665.6
COL11A1 Arterial calcification, of infancy, Pseudoxanthoma elasticum ENST00000263665.6
COL2A1 Fibrodysplasia ossificans progressiva ENST00000370096.3
COL4A1 Geleophysic dysplasia 1 ENST00000375820.4
IL6R Fibrochondrogenesis 1
Marshall syndrome
Stickler syndrome, type II
LRP1 Achondrogenesis, type II or hypochondrogenesis
Avascular necrosis of the femoral head
Czech dysplasia
Epiphyseal dysplasia, multiple, with myopia and deafness
Kniest dysplasia
Legg-Calve-Perthes disease
Osteoarthritis with mild chondrodysplasia
Otospondylomegaepiphyseal dysplasia
Platyspondylic skeletal dysplasia, Torrance type 1
SED congenita
SMED Strudwick type
Spondyloepiphyseal dysplasia, Stanescu type
Spondyloperipheral dysplasia
Stickler sydrome, type I, nonsyndromic ocular
Stickler syndrome, type I
PLOD3 Retinal arteries, tortuosity of
Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps

Lysyl hydroxylase 3 deficiency

SORT1 Brittle cornea syndrome 2 ENST00000256637.6


Clinical genetics and genomics laboratory 

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Telephone: +44(0)207 352 8121, ext 83009
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Useful documents

Molecular genetic testing request and consent form (pdf, 431KB)

Non-NHS molecular genetic testing request and consent form (pdf, 493KB)