1. Ehlers-Danlos syndrome and related disorders gene panel

Ehlers-Danlos syndrome and related disorders gene panel

May 04, 2018

Disease summary:

Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders caused by abnormalities in the structure, production, and/or processing of collagen 3, 9. The signs and symptoms of EDS are highly variable, ranging from mild to life-threatening complications. Major clinical features of EDS generally include joint hypermobility, skin hyperextensibility and tissue fragility. 

Ehlers-Danlos syndrome infographics

Autosomal recessive, autosomal dominant

1/5,000 – 1/200,000 2, 9, 13, 14

Major clinical features for classic Ehlers-Danlos syndrome (EDS) include1, 3:

  • Joint hypermobility with variable expression.
  • Skin hyperextensibility.
  • Widened atrophic scars.
  • Molluscoid pseudotumors over the bony prominences of the legs and arms.
  • Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pes planus).

Major clinical features for clinical diagnostics of EDS hypermobility include 9:

  • Joint hypermobility.
  • Soft skin with normal or only slightly increased extensibility and easy bruising.
  • Recurrent dislocation or subluxation of multiple joints.
  • Chronic joint, limb, and/or back pain.
  • Functional bowel disorders affecting 33%-67% of individuals with EDS, hypermobility types 10
  • Cardiovascular abnormalities, including autonomic dysfunction, Raynaud syndrome and acrocyanosis, aortic root dilation, and mitral valve prolapse.

Major diagnostic criteria for vascular type EDS 13:

  • Arterial aneurysms, dissection, or rupture.
  • Intestinal rupture.
  • Uterine rupture during pregnancy.
  • Family history of vascular type EDS.

                                                   

Major clinical features of EDS kyphoscoliotic type include the following 14:

  • Friable, hyperextensible skin, thin scars, easy bruising.
  • Generalized joint laxity.
  • Severe muscle hypotonia at birth.
  • Progressive scoliosis present at birth.
  • Scleral fragility and rupture of the globe. 

The diagnosis of EDS is based on the following:

  • Clinical evaluation and presence of characteristic clinical features (for each EDS subtype).
  • Collagen typing based on the skin biopsy.
  • Imaging studies including CT, MRI, angiography and ultrasound.
  • Positive family history of disease.
  • Pathogenic variant in EDS-associated genes (ADAMTS2, ATP7A, B3GALT6, B3GAT3, B4GALT7, CHST14, COL12A1, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, DSE, EFEMP2, ELN, FBLN5, FBN1, FKBP14, FLNA, GORAB, LTBP4, PLOD1, PRDM5, PYCR1, RIN2, SLC39A13, TNXB, ZNF469) 3, 9, 10, 13, 14.

There is no cure for Ehlers-Danlos syndrome and related disorders to date, but different types of treatment specifically designed for each EDS subtype can relieve symptoms 1.

  • Pain-reliever drugs (acetaminophen, ibuprofen, naproxen and others)
  • Blood pressure medication
  • Physical and occupational therapy
  • Surgical and other procedures (to repair joints, damaged skin etc.)
  • Cutis laxa caused by pathogenic variants in several genes, including ATP6V0A2, ATP7A, EFEMP2, ELN, and FBLN5.
  • Stickler syndrome caused by pathogenic variant in one of collagen-associated genes COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, or COL9A3.
  • Louys-Dietz Syndrome caused by pathogenic variant in TGFBR1, TGFBR2, SMAD3, or TGFB2.
  • Marfan syndrome caused by pathogenic variant of FBN1.
  • Occipital horn syndrome (OHS) and Menkes Disease caused by pathogenic variant in ATP7A.
  • Williams Syndrome caused by recurrent 7q11.23 contiguous gene deletion (including ELN gene)

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Ehlers-Danlos syndrome and related disorders using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Ehlers-Danlos syndrome and related disorders panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with Ehlers-Danlos syndrome and related disorders and overlapping phenotype or similar pathways.   

  • Individuals with a positive family history of Ehlers-Danlos syndrome and related disorders
  • Individuals with most common symptoms of Ehlers-Danlos syndrome and related disorders (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of Ehlers-Danlos syndrome and related disorders can allow for genetic counseling and may direct medical management.


There are several subtypes of EDS including the classic, hypermobility, vascular, kyphoscoliotic and progeroid types depending on the symptoms3, 9, 13, 14.  EDS may be inherited in an autosomal dominant or an autosomal recessive manner and so far pathogenic variants in several, collagen-associated genes (ADAMTS2, ATP7A, B3GALT6, B3GAT3, B4GALT7, CHST14, COL12A1, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, DSE, EFEMP2, ELN, FBLN5, FBN1, FKBP14, FLNA, GORAB, LTBP4, PLOD1, PRDM5, PYCR1, RIN2, SLC39A13, TNXB, ZNF469), have been reported in families with EDS 1, 2, 4


Overview of Ehlers-Danlos syndrome and related disorders and associated genes

EDS subtype (OMIM) Inheritance Gene (OMIM) Clinical features
EDS classic type
EDS type I; EDS type 2 formerly (130000) AD

COL1A1(120150)

COL5A1(120215)

COL5A2(120190) 

Easy bruising, mitral valve prolapse, premature rupture of the fetal membranes, premature birth
EDS-EFEMP2 related; Cutis laxa iB (614437) AR EFEMP2 (504633) Severe systemic connective tissue abnormalities, including emphysema, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels
EDS-Elastin related; Cutis laxa (123700); Supravalvular aortic stenosis (185500) AD ELN (130160) Aortic stenosis, loose skin, gastrointestinal diverticula, hernia, pulmonary artery stenosis, bronchiectasis, emphysema
EDS-FBLN5 related; Cutis laxa i1 (219100) AR FBLN5 (604580) Vascular anomalies, lung atelectasis and emphysema, diverticula of the gastrointestinal and genitourinary systems, joint laxity, developmental delay
EDS-LTBP4 related; Cutis laxa 1C (613177) AR LTBP4 (604710) Loose and/or wrinkled skin, prematurely aged appearance, impaired muscular, dermal and gastrointestinal development
EDS-PYRC1 related; De Barsy syndrome (614438) AR PYRC1 (179035) Aged appearance, cutis laxa, skeletal abnormalities, distinctive facial features, ophthalmologic abnormalities, intrauterine growth retardation
EDS subtype (OMIM) Inheritance Gene (OMIM) Clinical features
EDS hypermobility type
EDS type III; Benign hypermobility syndrome (130020) AD COL3A1 (120180) Striking joint hypermobility and minimal skin changes
EDS type VIB (formerly); Brittle cornea syndrome 1 (229200)  AR ZNF469 (612078) Corneal fragility, keratoglobus, blue sclerae, joint hyperextensibility
EDS related Brittle cornea syndrome 2 (614170)  AR PRDM5 (614161) Blue sclerae, corneal rupture after minor trauma, keratoconus, hyperelasticity of the skin, hypermobility of the joints
EDS due to tenascin deficiency (606408) AR TNXB (600985) Mild joint hypermobility, skin hyperextensibility, easy bruising
EDS-B3GAT3 related (245600) AR B3GAT3 (606374) Multiple joint dislocations, short stature, craniofacial dysmorphism, congenital heart defects
EDS myopathic type; Bethlem myopathy 2 616471) AR COL12A1 (120320) Hypotonia, proximal joint contractures, distal myopathy, delayed motor development
EDS cardiac valvular form (225320) AR COL1A2 (120160) Joint hypermobility, skin hyperextensibility, cardiac valvular defects
EDS spondylocheirodyplastic form (612350) AR SLC39A13 (608735) Hyperextensible thin skin, easy bruising, hypermobility of the small joints, protuberant eyes
EDS spondylocheirodyplastic type 2 (615349) AR B3GALT6 (615291) Short stature, developmental delay, craniofacial disproportion, generalized osteopenia, defective wound healing, hypermobile joints, hypotonic muscles, loose but elastic skin
EDS spondylocheirodyplastic type 1; EDS progeroid form (130070) AR B4GALT7 (604327) Progeroid appearance with wrinkled facies, curly and fine hair, scanty eyebrows and periodontitis
EDS subtype (OMIM) Inheritance Gene (OMIM) Clinical features
EDS vascular type
EDS type IV (130050)
EDS vascular type
AD COL3A1 (120180) Thin, translucent skin; easy bruising; characteristic facial appearance; arterial, intestinal, uterine fragility
EDS-FBN1 related; Marfan syndrome (154700) AD FBN1 (134797) Skeletal, vascular and ocular malformations (aortic aneurisms, aortic dissections, increased height, scoliosis, , joint laxity, craniofacial malformations, myopia) 
EDS subtype (OMIM) Inheritance Gene (OMIM) Clinical features
EDS kyphoscoliotic form
EDS kyphoscoliotic type 1 (225400) AR PLOD1 (153454) Kyphoscoliosis, joint laxity, muscle hypotonia
EDS kyphoscoliotic type 2 (614557) AR FKBP14 (614505) Severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment
EDS subtype (OMIM) Inheritance Gene (OMIM) Clinical features
EDS-other forms
EDS arthrochalasia type (VII 7A/7B) (130060)
EDS dermatosparaxis type (VIIC) (225410)
AD, AR COL1A1 (120150)

COL1A2 (120160)

ADAMTS2 (604539)
Congenital bilateral hip dislocation, severe joint hypermobility, tissue fragility, skin hyperextensibility
EDS type IX (304150)
Occipital horn syndrome
XLR ATP7A (300011) Hyperelastic bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, skeletal abnormalities
EDS musculocontractural type 1 (601776) AR CHST14 (608429) Craniofacial dysmorphism, hyperextensible thin skin, atrophic scarring, easy bruising, small joint hypermobility, hypotonia
EDS musculocontractural type 2 (615539) AR DSE (605942) Progressive multisystem fragility, joint dislocations, skin hyperextensibility, subcutaneous hematomas; cardiac complications, myopathy, muscle hypoplasia, muscle weakness
EDS and periventricular nodular heterotopia (300049) XLD FLNA (300017) Seizures, cardiovascular abnormalities, cutaneous and joint abnormalities 
EDS-GORAB related; Geroderma osteodysplasticum (231070) AR GORAB (607983) Osteoporosis, lax skin, mandibular prognathism, precocious aging, dental and facial abnormalities
RIN2-syndrome; MACS syndrome (613075) AR RIN2 (610222) Severe progressive scoliosis, facial coarsening, gingival hypertrophy, and skin and joint hyperlaxity