Scientific Background
ARTHROCHALASIA EHLERS-DANLOS SYNDROME
The very rare arthrochalasia EDS subtype (aEDS) is inherited in an autosomal dominant manner. It is characterized by an extreme, generalized hypermobility of the joints associated with joint subluxations as well as a congenital, bilateral hip dislocation. Additional symptoms may include muscle hypotonia, short stature, osteopenia, kyphoscoliosis, and velvety, hyperextensible skin. Unlike other EDS subtypes, mild dysmorphic signs such as hypertelorism, bilateral epicanthal folds, wide fontanelles, and micrognathia may occur.
aEDS is caused by variants in the collagen genes COL1A1 and COL1A2, which encode the α1- and α2-chains of type I collagen predominant in skin and bone. Almost all of the described variants affect exon 6 of the COL1A1 or COL1A2 genes. These are primarily splice variants, removing the recognition site for cleavage of the N-terminal propeptides in the α-chains of type I procollagen. In addition, a genomic deletion has been described in both the COL1A1 and the COL1A2 gene, which includes exon 6 and also eliminates the recognition site for cleavage of the N-terminal propeptides. To date, outside these defined regions, only a partial duplication of the COL1A2 gene has been described in aEDS; the affected patient exhibited additional symptoms of osteogenesis imperfecta. In total, four different pathogenic variants in the COL1A1 gene and 12 different pathogenic variants in the COL1A2 gene have been described in aEDS. Incompletely processed procollagen chains can also be detected biochemically and a characteristic ultrastructure seen by electron microscopy.
2 genes: COL1A1, COL1A2
References
Malfait et al. 2017, Am J Med Genet C 175:8 / Brady et al. 2017, Am J Med Genet C 175:70 / Klaassens et al. 2012, Clin Genet 82:121 / Giunta et al. 2008, Am Med Genet 146A:1341 / Raff et al. 2000, Hum Genet 106:19 / Nicholls et al. 2000, J Med Genet 37:E33 / Byers et al. 1997, Am J Med Genet 72:94
CLASSICAL EHLERS-DANLOS SYNDROME
Classical EDS (cEDS) is inherited in an autosomal dominant manner. It is the second most common EDS subtype with a prevalence of 1:20,000. Initial descriptions differentiated between EDS gravis and EDS mitis, which differ only in severity. According to the 2017 classification, significant skin hyperextensibility with atrophic scarring (cigarette paper scars) and generalized joint hypermobility are the main clinical criteria. Secondary criteria include easy bruising, soft velvety skin, tissue lesions, molluscoid pseudotumors, subcutaneous spheroids, hernias, epicanthal folds, musculoskeletal complications due to the hypermobility and complications during surgery due to tissue fragility.
Variants in the COL5A1 and COL5A2 genes, which encode the α1- and α2-chain of type V collagen, are the molecular cause of cEDS in patients. Variants in the COL5A1 gene are present in about 75% of patients, while variants in the COL5A2 gene have been described in about 14% of patients. According to the 2017 classification, the minimum requirement for a genetic diagnosis of cEDS is the presence of the major clinical criterion of skin hyperextensibility with atrophic scarring, either in combination with the second major clinical criterion of generalized joint hypermobility, or with at least three minor clinical criteria. Pathogenic variants in the COL5A1 and COL5A2 genes have be detected in 90% of patients in whom all major clinical criteria were met. The majority of all COL5A1 and COL5A2 variants lead to premature translational stop and subsequently to a null allele. Approximately 30% of all COL5A1 variants and 40% of all COL5A2 variants are structural, affecting glycine in the triple helix. Genomic deletions have not yet been identified in the COL5A2 gene, and the literature describes only four genomic deletions and one genomic duplication in the COL5A1 gene.
A clinical diagnosis of cEDS can be confirmed by the detection of a pathogenic variant in the COL5A1 or COL5A2 gene. In the absence of molecular genetic evidence, a characteristic ultrastructure with cauliflower-like changes seen in the electron microscopic examination of the collagen fibrils of a skin biopsy may support the clinical diagnosis of cEDS.
Variants in the COL1A1 gene have also been identified in approximately 1% of patients with cEDS. If the variants affect arginine substitutions, then they are often associated with vascular involvement, whereas EDS patients with glycine substitutions, other amino acid substitutions, or translational stop mutations in the COL1A1 gene show additional symptoms of osteogenesis imperfecta.
3 genes: COL1A1, COL5A1, COL5A2
References
Malfait et al. in: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® (Updated 2018 Jul 26) / Malfait et al. 2017, Am J Med Genet C 175:8 / Bowen et al. 2017, Am J Med Genet C 175:27 / Mayer et al. 2013, Eur J Hum Genet 21, update 2012 / Ritelli et al. 2013, Orphanet J Rare Dis 8:58 / Symoens et al. 2012, Hum Mutat 33:1485 / Mitchell et al. 2009, Hum Mutat 30:995 / Malfait et al. 2007, Genet Med 12:597 / Hausser et al. 1994, Hum Genet 93:394
PERIODONTAL EHLERS-DANLOS SYNDROME
The autosomal dominantly inherited periodontal EDS (pEDS) is characterized by severe, early onset periodontitis. Clinical symptoms start in childhood with extensive gingivitis leading to destruction of the periodontium and premature tooth loss in adolescence. Other clinical features include pretibial hyperpigmentation, acrogeria, vulnerable skin and gums, abnormal scarring, generalized joint hypermobility, and easy bruising. Rupture of arteries and internal organs and CNS involvement in the form of microangiopathy and leukoencephalopathy have also been described in individual cases.
In 2003, a candidate region was located on chromosome 12p13.1, but no gene was identified. In 2016, complementary exome analysis of 19 families identified pathogenic variants in C1R in 15 families and in C1S in two families. The C1R and C1S genes, which are directly adjacent in region 12p13.1, encode the C1r and C1s subunits of the complement pathway. The proteins form a heterotetramer that combines with six C1q subunits. The pathogenic variants identified so far lead to intracellular retention of the complement complex and endoplasmic reticulum enlargement.
2 genes: C1R, C1S
References
Kapferer-Seebacher et al. 2019, Neurogenetics 20:1 / Wu et al. 2018, J Clin Periodontol 45:1311 / Brady et al. 2017, Am J Med Genet C 175:70 / Kapferer-Seebacher et al. 2017, J Clin Periodontol 44:1088 / Kapferer-Seebacher et al. 2016, Am J Hum Genet 99:1005 / Reinstein et al. 2013, Eur J Hum Genet 21:233 / Rahman et al. 2003, Am J Hum Genet 73:198 / Hartsfield et al. 1990, Am J Med Genet 37:465 / Stewart et al. 1977, Birth Defects Orig Art Ser XIII:85
VASCULAR EHLERS-DANLOS SYNDROME
Vascular EDS (vEDS) has a high risk of rupture of arteries, uterus and internal organs with fatal bleeding. Type III collagen represents an important component of the walls of arteries and internal organs (up to 45%), so that these tissues are particularly affected in vEDS. The main clinical criteria according to the 2017 classification are arterial rupture at a young age, spontaneous perforation of the sigmoid colon, uterine rupture during the third trimester, AV fistulas between the carotid artery and cavernous sinus, and a positive family history with a confirmed pathogenic COL3A1 variant. The mode of inheritance is autosomal dominant, and the prevalence is estimated at 1:50,000.
To date, only pathogenic variants in the COL3A1 gene have been published as found in patients with vEDS; biochemically this results in altered synthesis, structure, or secretion of type III procollagen. The composition of the identified types of nucleotide alterations in the COL3A1 gene includes glycine substitutions within the triple helix domain of the pro-α1 (III) chain (approximately 65%), variants leading to premature translational arrest and resulting in structurally altered or unstable polypeptides (30%), and genomic deletions and complex rearrangements affecting whole or multiple exons (less than 5%). The type of variant has an impact on the clinical course: patients with null alleles have a later onset of vascular complications and increased life expectancy compared with patients carrying other variants, whereas patients with glycine substitutions and exon skipping variants have the least favorable prognosis. The localization of the variant within the gene has no influence.
Clinical indicators for the genetic diagnosis of suspected vEDS are a positive family history and the presence of arterial rupture or dissection before the age of 40 years, spontaneous sigmoid perforation, or spontaneous pneumothorax. The clinical diagnosis of vEDS can be confirmed by detection of a pathogenic variant in the COL3A1 gene or by the altered synthesis, structure or secretion of type III procollagen in cultured skin fibroblasts. Although COL3A1 is the only altered gene in vEDS, the genetic detection rate often remains low because the clinical phenotype in patients is frequently incomplete. In the literature, the detection rate of the COL3A1 gene is 95-100% for biochemically detected, structurally altered type III collagen. In patients with a clinical diagnosis of vEDS without evidence of a pathogenic COL3A1 variant, analysis of other genes in the TGFß signal transduction pathway may be considered.
1 gene: COL3A1
References
Byers et al. in: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews® (updated 2019 Feb 21) / Kuivaniemi and Tromp 2019, Gene 707:151 / Malfait et al. 2017, Am J Med Genet C 175:8 / Byers et al. 2017, Am J Med Genet C 175:40 / Frank et al. 2015, Eur J Hum Genet 23:1657 / Pepin et al. 2014, Genet Med 16:881 / Mayer et al. 2013, Eur J Hum Genet 21, update 2012 / Ong et al. 2012, Virchows Arch 460:637 / Germain 2007, Orphanet J Rare Dis 2:32 / Pepin et al. 2000, N Engl J Med 342:673
MYOPATHIC EHLERS-DANLOS SYNDROME
Myopathic EDS (mEDS) is characterized by muscle weakness that manifests in childhood with proximal contractures of the large joints and distal joint hypermobility. Typically, muscle weakness improves in young adulthood, although it may deteriorate again in the fourth decade of life. The spectrum of disorders characterized by muscle weakness, hypotonia, myopathy, and connective tissue symptomatology was originally associated with collagen type VI disorders.
Pathogenic variants in COL12A1, which encodes the α1-chain of type XII collagen, are the molecular cause of mEDS. Collagen XII is present as a homotrimer on the surface of type I collagen fibers. It forms a link between type I collagen fibers and extracellular matrix components such as decorin, fibromodulin, and tenascin. To date, mEDS has been described in both an autosomal dominantly inherited form with heterozygous missense variants and an autosomal recessively inherited form with homozygous frameshift variants.
1 gene: COL12A1
References
Delbaere et al. 2019, Genet Med 22:112 / Jezela-Stanek et al. 2019, Clin Genet 95(6):736 / Punetha et al. 2017, Muscle Nerve 55:277 / Brady et al. 2017, Am J Med Genet C 175:70 / Zou et al. 2014, Hum Mol Genet 23:2339 / Hicks et al. 2014, Hum Mol Genet 23:2353
