Ehlers-Danlos Syndrome and Related Disorders Gene Panel
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.
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||15|
|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||42|
|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||71|
|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||36|
|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|
|SLC39A13||608735||Ehlers-Danlos syndrome spondylodysplastic type 3||AR||0|
|TNXB||600985||classic-like Ehlers-Danlos syndrome; Vesicoureteral reflux type 8||AD, AR||78|
|ZNF469||612078||Brittle cornea syndrome||AR||5|