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].

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]. 

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].

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]. 

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]. 

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]. 

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].

Other genes included in the aortopathy and vasculopathy NGS panel

Clinical genetics and genomics laboratory 

Ground floor (level 2), Sydney wing, Royal Brompton Hospital, Sydney Street, London, SW3 6NP

Telephone: +44(0)207 352 8121, ext 83009
Email: rbh-tr.genomics@nhs.net or geneticslab@rbht.nhs.uk 

Opening hours: Monday to Friday, 9am to 5pm

Head of laboratory: Dr Deborah Morris-Rosendahl

Useful documents

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

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