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


Table 1: Overview of genes included in Ehlers-Danlos syndrome and related disorders panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ADAMTS2 604539 Ehlers-Danlos syndrome dermatosparaxis type AR 6
ATP7A 300011 X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease XLR 16
B3GALT6 615291 Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures; Ehlers-Danlos syndrome spondylodysplastic type 2 AR 8
B3GAT3 606374 Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects AR 5
B4GALT7 604327 Ehlers-Danlos syndrome spondylodysplastic type 1 AR 2
CHST14 608429 Ehlers-Danlos syndrome musculocontractural type 1 AR 2
COL12A1 120320 Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 AD 16
COL1A1 120150 Caffey disease; Ehlers-Danlos syndrome arthrochalasia type 1; osteogenesis imperfecta type 1; osteogenesis imperfecta type 2; osteogenesis imperfecta type 4; OSTEOPOROSIS; osteogenesis imperfecta type 3 AD 78
COL1A2 120160 osteogenesis imperfecta type 2; osteogenesis imperfecta type 4; OSTEOPOROSIS; Ehlers-Danlos syndrome, cardiac valvular form; osteogenesis imperfecta type 3; Ehlers-Danlos syndrome arthrochalasia type 2 AD, AR 61
COL3A1 120180 vascular-type Ehlers-Danlos syndrome AD 40
COL5A1 120215 Ehlers-Danlos syndrome classic type 1 AD 114
COL5A2 120190 Ehlers-Danlos syndrome classic type 2 AD 44
DSE 605942 Ehlers-Danlos syndrome musculocontractural type 2 AR 2
EFEMP2 604633 Cutis laxa, autosomal recessive, type IB AR 2
ELN 130160 Cutis laxa, autosomal dominant 1, ADCL1; Supravalvar aortic stenosis AD 3
FBLN5 604580 Cutis laxa, autosomal recessive, type IA AD, AR 0
FBN1 134797 Marfan syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2 AD 73
FKBP14 614505 Ehlers-Danlos syndrome kyphoscoliotic type 2 AR 4
FLNA 300017 Congenital short bowel syndrome; Heterotopia, periventricular / X-linked periventricular heterotopia; Terminal osseous dysplasia; FG syndrome 2; Otopalatodigital syndrome, type II; Frontometaphyseal dysplasia; Melnick-Needles syndrome; otopalatodigital syndrome type I; Cardiac valvular dysplasia, X-linked XL, XLD, XLR 34
GORAB 607983 geroderma osteodysplasticum AR 1
LTBP4 604710 Cutis laxa, autosomal recessive, type IC AR 7
PLOD1 153454 Ehlers-Danlos syndrome kyphoscoliotic type 1 AR 26
PRDM5 614161 Brittle Cornea Syndrome 2 AR 2
PYCR1 179035 autosomal recessive cutis laxa type 2B AR 2
RIN2 610222 MACS syndrome AR 1
SLC39A13 608735 Ehlers-Danlos syndrome spondylodysplastic type 3 AR 1
TNXB 600985 classic-like Ehlers-Danlos syndrome; Vesicoureteral reflux type 8 AD, AR 77
ZNF469 612078 Brittle cornea syndrome AR 6