OVERVIEW

There are more than 200 hereditary diseases of the connective tissue that can affect the look and growth of skin, bones, joints, heart, blood vessels, lungs, eyes, and ears. Common hereditary connective tissue disorders include: Ehlers-Danlos syndrome (loose joints, easy bruising and stretchy skin), Marfan syndrome (unusually tall and thin with long extremities), Cutis laxa (inelastic, wrinkled skin), Loeys-Dietz-syndrome (scoliosis, loose joints, easy bruising skin) and Osteogenesis imperfecta (easy breaking bones). Most of these disorders are present at birth. Connective tissue diseases can have aortic involvement leading to aneurysms or aneurysm ruptures. Early identification of individuals at risk can help establish the right clinical management plan.

We offer comprehensive and syndrome-specific panels testing for diseases of the connective tissue. The test can offer a molecular genetic diagnosis of a connective tissue disorder that is observed or predicted in you/your child or a family member.

IMPORTANCE OF GETTING TESTED

If you or a family member has a risk of a disease of the connective tissue, identifying the cause can help to take actions to improve the outcome of the disorder. Additionally, family members can be informed and encouraged to also get tested. Our genetic counsellors can provide medical advice.

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You have a family history of connective tissue diseases
and want to know if you are a carrier or
estimate the risk for your child

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You/your child has a clinical diagnosis of
a connective tissue disease and
want to confirm/differentiate

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You need a prophylactic aortic surgery and
want to determine the right timing

POSSIBLE OUTCOMES OF THE TEST

A molecular genetic diagnostic report outlining the results of the sequencing analysis is provided. Changes in DNA sequences (variants) can be detrimental and lead to the development of a cardiac or aortic disorder, including asymptomatic disorders that develop later in life. We will report pathogenic and likely pathogenic variants as well as variants of unknown significance.
Pathogenic and likely pathogenic variants mean the genetic cause of the observed symptoms has been identified and may help determine the right treatment and management plan.
Variants of unknown significance means there was not enough evidence to classify the variant as either pathogenic or neutral. Annual variant reclassification and testing family members is recommended.
It is important to note that a negative result does not guarantee the absence of a disorder or that the disorder does not have a genetic cause. Genetic testing is an evolving field and may not detect all variants or there may not currently be enough evidence to classify all variants that lead to an inherited disease.

MEDICAL GENETIC COUNSELLING

We provide expert medical genetic counselling as part of a genetic testing journey. Genetic counselling is a process of communication that supports patients and their relatives before and after genetic testing. It is educational, impartial and nondirective. Prior to any genetic test, genetic counsellors will obtain a detailed family history, explain the method of testing that will be used, its risks and benefits, the limitations of the diagnosis and the implications of making a genetic diagnosis (Elliott and Friedman, 2018, Nat Rev Genet 19:735).

Upon receiving the genetic test results, genetic counselling can help the specialist physician and the patient to interpret them. They can be advised of the consequences of the results including the probability of developing the genetic disorder or passing it on to children, as well as ways to prevent, avoid or reduce these risks (Yang and Kim, 2018, Ann Lab Med 38:291). Our goal of counselling is to provide the patient with greater knowledge and thus, a better understanding of the results and the ability to make a more informed decision.

ACCEPTED MATERIAL

1 ml EDTA Blood

TURNAROUND TIME

15-25 working days

TECHNOLOGY

DNA is isolated and next generation sequencing is performed on all coding exons and conserved intronic regions. Single base pair changes, small deletions and duplications and copy number variants (CNV) are identified. Sequencing runs result in a Quality Score of >30 (accuracy >99.9%) in at least 75% of all bases with a coverage of >20-fold. CNV detection sensitivity is 76.99% and precision is 62.59% (with GC limitation between 0.4 and 0.6 per target sensitivity is 77.04% and precision is 84.10%). Variant classification is performed following ACMG guidelines (Richards et al. 2015, Genet Med 17:405; Kearney et al. 2011, Genet Med 13:680).

TEST METHODOLOGY
Sequencing

Next generation
sequencing (Illumina)

Enrichment

Twist Human Core
Exome plus Ref Seq
Spikeln

SNV and CNV data anlaysis

Illumina DRAGEN
Bio-IT Platform

Data Evaluation

VarSeq by
GoldenHelix

Reference Genome

hg38, NCBI GR38

Quality Criteria

>30 (precision >99,9%)
in min. 75% of bases

SNV detection sensitivity

99.92-99.93%; confirmation of reported SNV with Sanger
sequencing, data analysis with
SeqPilot

Classification of variants

Richards et al. 2015, Genet Med
17:405; Ellard et al. “ACGS Best
Practice Guidelines for Variant
Classification 2020″

in silico algorithms

MaxEntScan,
SpliceSiteFinder-like,
REVEL

Databases

HGMD Professional
release, ClinVar,
gnomAD

OUR TESTS

Achondrogenesis type 2

Genes: COL2A1

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Achondroplasia

Genes: FGFR3

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Apert syndrome

Genes: FGFR2

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Bicuspid aortic valve with risk of aortic valve stenosis and dilatation

Genes: GATA5, NOTCH1, ROBO4, SMAD6

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Contractural arachnodactyly, congenital

Genes: FBN2

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CRANIOSYNOSTOSIS (extended)

Genes: ALX4, BMP4, CCBE1, CDC45, CEP120, EFNB1, ERF, ESCO2, FGFR1, FGFR2, FGFR3, FREM1, GLI3, IFT122, IFT140, IFT43, IL11RA, IMPAD1, IRX5, KRAS, MEGF8, MSX2, MYH3, P4HB, POR, RAB23, RECQL4, SCARF2, SEC24D, SKI, SMAD6, SPECC1L, STAT3, TCF12, TGFBR1, TGFBR2, TWIST1, WDR19, WDR35, ZIC1

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CRANIOSYNOSTOSIS (standard)

Genes: FGFR1, FGFR2, FGFR3, TCF12, TWIST1

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Crouzon syndrome

Genes: FGFR2

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Crouzon syndrome with acanthosis nigricans

Genes: FGFR3

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Cutis laxa

Genes: ALDH18A1, ATP6V0A2, ATP6V1A, ATP6V1E1, EFEMP2, ELN, FBLN5, LTBP4, PYCR1

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Ectopia lentis

Genes: ADAMTSL4, FBN1, LTBP2

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Ehlers-Danlos syndrome, arthrochalasia type

Genes: COL1A1, COL1A2

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Ehlers-Danlos syndrome, autosomal dominant subtypes

Genes: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2

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Ehlers-Danlos syndrome, autosomal recessive subtypes

Genes: ADAMTS2, AEBP1, B3GALT6, B4GALT7, CHST14, COL1A2, DSE, FKBP14, PLOD1, SLC39A13

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Ehlers-Danlos syndrome, cardiac-valvular

Genes: COL1A2

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Ehlers-Danlos syndrome, classical

Genes: COL1A1, COL5A1, COL5A2

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Ehlers-Danlos syndrome, classical-like

Genes: AEBP1, TNXB

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Ehlers-Danlos syndrome, dermatosparaxis

Genes: ADAMTS2

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Ehlers-Danlos syndrome, kyphoscoliotic

Genes: FKBP14, PLOD1

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Ehlers-Danlos syndrome, musculocontractural

Genes: CHST14, DSE

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Ehlers-Danlos syndrome, myopathic

Genes: COL12A1

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Ehlers-Danlos syndrome, periodontal

Genes: C1R, C1S

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Ehlers-Danlos syndrome, rare types and differential diagnosis

Genes: C1R, C1S, COL12A1, COL6A1, COL6A2, COL6A3, EMILIN1, FLNA, PHYKPL, PIEZO2, PLOD3, PRDM5, SLC2A10, ZNF469

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Ehlers-Danlos syndrome, vascular

Genes: COL3A1

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Geleophysic dysplasia

Genes: ADAMTSL2, FBN1, LTBP3

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Hemorrhage, intracerebral

Genes: COL4A1, COL4A2

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Hypochondrogenesis

Genes: COL2A1

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Hypochondroplasia

Genes: FGFR3

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Kniest syndrome

Genes: COL2A1

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Langer mesomelic dysplasia

Genes: SHOX

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Léri-Weill dyschondrosteosis

Genes: SHOX

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Loeys-Dietz syndrome

Genes: SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2

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Lujan-Fryns syndrome

Genes: MED12, UPF3B, ZDHHC9

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Marfan syndrome (MFS)

Genes: FBN1, TGFBR1, TGFBR2

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MARFAN-LIKE DISORDERS

Genes: ADAMTS10, ADAMTS17, ADAMTSL2, ADAMTSL4, FBN1, FBN2, LTBP2, LTBP3, MED12, SKI, UPF3B, ZDHHC9

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Marshall syndrome

Genes: COL11A1

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Meester-Loeys syndrome

Genes: BGN

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Metaphyseal chondrodysplasia, Schmid type

Genes: COL10A1

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Muenke syndrome

Genes: FGFR3

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OSTEOGENESIS IMPERFECTA (extended)

Genes: BMP1, COL1A1, COL1A2, CRTAP, FKBP10, IFITM5, P3H1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, TMEM38B, WNT1

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OSTEOGENESIS IMPERFECTA, AUTOSOMAL DOMINANT (standard)

Genes: COL1A1, COL1A2, IFITM5, WNT1

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OSTEOGENESIS IMPERFECTA, AUTOSOMAL RECESSIVE (standard)

Genes: BMP1, CRTAP, FKBP10, P3H1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, TMEM38B, WNT1

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Otospondylomegaepiphyseal dysplasia (OSMED)

Genes: COL11A2

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Pfeiffer syndrome

Genes: FGFR1, FGFR2

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Pseudoxanthoma elasticum

Genes: ABCC6

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ROBINOW SYNDROME

Genes: DVL1, DVL3, NXN, ROR2, WNT5A

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Saethre-Chotzen syndrome

Genes: TWIST1

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SHORT RIB THORACIC DYSPLASIA (extended)

Genes: CEP120, CSPP1, DYNC2H1, DYNC2LI1, EVC, EVC2, IFT122, IFT140, IFT172, IFT43, IFT52, IFT80, KIAA0586, NEK1, TCTN3, TTC21B, WDR19, WDR34, WDR35, WDR60

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SHORT RIB THORACIC DYSPLASIA (standard)

Genes: DYNC2H1, IFT80, NEK1, TTC21B, WDR34

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Shprintzen-Goldberg syndrome

Genes: SKI

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Spondyloepiphyseal dysplasia

Genes: COL2A1

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STICKLER SYNDROME

Genes: COL11A1, COL11A2, COL2A1, COL9A1, COL9A2

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Thanatophoric dysplasia

Genes: FGFR3

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Thoracic aortic aneurysm and dissection (TAAD)

Genes: ACTA2, BGN, CBS, COL1A1, COL3A1, COL4A5, COL5A1, COL5A2, EFEMP2, ELN, EMILIN1, FBLN5, FBN1, FBN2, FLNA, FOXE3, GATA5, LOX, LTBP3, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, ROBO4, SKI, SLC2A10, SMAD2, SMAD3, SMAD4, SMAD6, TGFB2, TGFB3, TGFBR1, TGFBR2

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Thoracic aortic disease, nonsyndromic

Genes: ACTA2, FOXE3, GATA5, LOX, LTBP3, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, ROBO4, SMAD6, TGFBR1, TGFBR2

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Thoracic aortic disease, rare, syndromic

Genes: BGN, CBS, COL1A1, COL3A1, COL5A1, COL5A2, EMILIN1, FBN1, FBN2, FLNA, PLOD1, SKI, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2

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Thoracic aortic disease, rare, syndromic, recessive, cutis laxa

Genes: EFEMP2, ELN, FBLN5, SLC2A10

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Type 1 fibrillinopathies

Genes: FBN1

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Weill-Marchesani syndrome

Genes: ADAMTS10, ADAMTS17, FBN1, LTBP2

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OUR NETWORK