Download Stickler Syndrome Genetics

STICKLER
SYNDROME
Corrine Fillman, M.S., C.G.C.
Connective Tissue Gene Tests
(CTGT)
6580 Snowdrift Road, Suite 300
Allentown, PA 18106
OUTLINE
• Stickler Syndrome
– Clinical Findings
– Genes
– Connective Tissue & Collagen
– Autosomal Dominant Stickler syndrome
• Marshall syndrome
– Autosomal Recessive Stickler syndrome
• How is Stickler & Marshall Syndrome
Diagnosed?
– Clinical Diagnosis
– Molecular Diagnosis-CTGT
2
STICKLER SYNDROME
AFFECTS MANY PARTS OF THE BODY:
Eyes:
Nearsightedness
Cataracts
Retinal detachment
Ears:
Hearing Loss
Joints:
Early-onset arthritis
Oral/Facial:
Cleft palate
Bifid uvula
Small chin
Pierre-Robin sequence
Flat cheeks
Flat nasal bridge
Bones:
Chondrodysplasia
3
STICKLER SYNDROME
A GENETIC DISORDER

Genetic disorder
A condition that can be passed from one generation to the next
within a family
 A condition caused by a defect (mutation) in a gene

4
STICKLER SYNDROME
GENES
COL11A1
COL9A2
COL11A2
COL2A1
COL9A1
COL9A3
5
STICKLER SYNDROME
A CONNECTIVE TISSUE DISORDER
– The genes associated with Stickler syndrome
are responsible for making proteins called
collagens. Specifically collagen type II, XI & IX.
– There are many types of collagens and
collagens are found throughout the body in our
connective tissue.
– Connective tissue is a material that provides
strength and support for organs and tissues.
– The collagen types associated with Stickler
syndrome are found primarily in cartilage, part
6
of the clear gel that fills the eyeball (the
vitreous) and the inner ear.
STICKLER SYNDROME
COLLAGEN PROTEIN
The collagen protein is made of 3 protein chains wrapped around one
another like a rope.
Collagen II protein is made of 3 identical protein chains made from
the COL2A1 gene.
Collagen XI protein is made of 3 different protein chains.
1 chain is made from the COL11A1 gene
1 chain is made from the COL11A2 gene
1 chain is made from the COL11A3 gene
Collagen IX protein is made of 3 different protein chains.
1 chain is made from the COL9A1 gene
1 chain is made from the COL9A2 gene
1 chain is made from the COL9A3 gene
7
STICKLER SYNDROME
AUTOSOMAL DOMINANT
• The majority of individuals with Stickler
syndrome have autosomal dominant
Stickler syndrome.
• The genes associated with autosomal
dominant Stickler syndrome are
COL2A1, COL11A1 and COL11A2.
• First-degree relatives (children, siblings
and parents) have a 50% chance of
also having Stickler syndrome.
8
STICKLER SYNDROME
TYPES
There are differences in an individual’s clinical findings depending upon the
affected gene and mutation
Stickler syndrome, type I
•80-90% of individuals with Stickler syndrome have mutations in
the COL2A1 gene.
•Autosomal dominant inheritance.
•Individuals may have a “membranous” type 1 vitreous anomaly.
•Mutations in the COL2A1 gene cause Stickler syndrome, type I.
•Individuals with mutations in exon 2 of the COL2A1 gene have an
ocular variant of Stickler syndrome.
– Individuals may present with typical eye findings including an
empty vitreous and/or early-onset retinal detachment but
there are minimal or absent findings in the ears, bones, joints
and oral/facial structures.
9
THERE ARE
DIFFERENCES IN AN
INDIVIDUAL’S
CLINICAL FINDINGS
DEPENDING
UPON THE AFFECTED
GENE AND MUTATION
In the case of COL2A1, the type of mutation and the location within the gene
will result in different clinical findings:
COL2A1 mutations are associated with more than one disorders
including:
Stickler syndrome, type I
Stickler syndrome, type I, nonsyndromic ocular
Other Conditions:
Achondrogenesis, type II / Hypochondrogenesis
Spondyloepiphyseal dysplasia congenita
Spondyloepimetaphyseal dysplasia, Strudwick type
Kniest dysplasia
Spondyloepiphyseal dysplasia late onset
Avascular necrosis of femoral head
Early-onset osteoarthritis
11
STICKLER SYNDROME
TYPES
There are differences in an individual’s clinical findings depending upon the
affected gene and mutation
Stickler syndrome, type II
• Mutations in the COL11A1 gene cause Stickler
syndrome, type II.
• 10-20% of individuals with Stickler syndrome
have mutations in the COL11A1 gene.
• Autosomal dominant inheritance.
• Individuals may have a “beaded” type 2 vitreous 12
anomaly.
THERE ARE DIFFERENCES IN AN
INDIVIDUAL’S CLINICAL FINDINGS
DEPENDING UPON THE AFFECTED GENE
AND MUTATION
In the case of COL11A1, the type of mutation and the location within the
gene will result in different clinical findings:
COL11A1 mutations are associated with more than one disorder including:
Stickler syndrome, type II
Other Conditions:
Marshall syndrome
Fibrochondrogenesis
13
MARSHALL SYNDROME
• Shares many features in common with
Stickler syndrome including:
nearsightedness, retinal detachment,
hearing loss, cleft palate and Pierre-Robin
sequence.
• In addition, patients may have early-onset
hearing loss, short stature, abnormalities in
cranial ossification, and more pronounced
facial features including markedly flat
cheeks with a flat nasal bridge and a short
upturned nose.
• Mutations in the COL11A1 gene cause
Marshall syndrome.
• Mutations in this gene also cause Stickler
syndrome, type II.
• Autosomal dominant inheritance and firstdegree relatives (children, siblings &
parents) have a 50% chance of also having
Marshall syndrome.
Annunen et al., 1999. Am J Hum Genet 65:974-983.
A -B-Stickler syndrome14
C-F- Marshall syndrome
STICKLER SYNDROME
TYPES
There are differences in an individual’s clinical findings depending upon the
affected gene and mutation
Stickler syndrome, type III
• Mutations in the COL11A2 gene cause a nonocular form of Stickler syndrome.
• Autosomal dominant inheritance.
• Individuals have cleft palate and/or Pierre-Robin
sequence, hearing loss and early-onset
osteoarthritis.
• Individuals do not have eye findings typically
associated with Stickler syndrome.
15
THERE ARE DIFFERENCES IN AN
INDIVIDUAL’S CLINICAL FINDINGS
DEPENDING UPON THE AFFECTED GENE
AND MUTATION
In the case of COL11A2, the type of mutation and the location within
the gene will result in different clinical findings:
COL11A2 mutations are associated with more than one disorder
including:
Stickler syndrome, type III
Other Conditions:
Otospondylomegaepiphyseal dysplasia
Weissenbacher-Zweymuller syndrome
16
STICKLER SYNDROME
AUTOSOMAL RECESSIVE
• It is not known how many
individuals with Stickler
syndrome have autosomal
recessive inheritance.
• Mutations in the COL9A1,
COL9A2 and COL9A3 genes
cause Stickler syndrome,
autosomal recessive.
• Siblings of an affected
individual have a 25% chance
of also having Stickler
17
syndrome and a 50% chance
of being an unaffected carrier.
STICKLER SYNDROME
AUTOSOMAL RECESSIVE
•2006-COL9A1
Van Camp et al., 2006. Am J Hum Genet 79:449-457.
•Severe myopia, vitreoretinal degeneration,hearing loss, chondrodysplasia
•2010- COL9A2 & COL9A3-Canine studies
Goldstein et al., 2010. Mamm Genome 21:398-408.
•Oculoskeletal dysplasia similar to STL1 & STL2 segregates as an autosomal
recessive trait in Labrador Retriever and Samoyed dog breeds
•Vitreous dysplasia, retinal detachment, cataracts, short-limb dwarfism
•2011- COL9A2
Baker et al., 2011. Am J Med Genet Part A 9999: 1-5.
•Severe myopia,vitreoretinal degeneration, retinal detachment, hearing loss
18
STICKLER SYNDROME
AUTOSOMAL RECESSIVE
19
Baker et al., 2011. Am J Med Genet Part A 9999: 1-5
HOW IS STICKLER SYNDROME AND
MARSHALL SYNDROME DIAGNOSED?
• Clinical Diagnosis: made by evaluating a patient’s medical
and family history and having a thorough physical exam by a
physician and/or specialists.
– A physician can use published literature and references that
describe the clinical findings to help make a diagnosis.
– There is a wide range of clinical findings, and individuals in the
same family may have different findings and varying degrees of
severity.
• Molecular Diagnosis (genetic testing): made by identifying a
mutation in one of the associated genes.
– Molecular testing is available in CLIA approved laboratories and
requires a blood sample from the individual suspected to have
a diagnosis.
– Can confirm a suspected clinical diagnosis.
– Results from a molecular diagnosis can be used for
surveillance and management.
– Results can be used to confirm or rule out the diagnosis in at 21
risk family members.
CONNECTIVE TISSUE GENE
TESTS
Director of Research, Development and Technology
Leena Ala-Kokko, M.D., Ph.D.
CEO and Medical Director
James Hyland, M.D., Ph.D.
•CTGT was established in June, 2004 and is located in Allentown, PA.
•About 20 employees.
•CLIA & CAP certified.
•Currently test for over 100 different genetic disorders.
•Offer many different technologies for testing.
•CTGT in continually adding new tests and developing new technologies.
•CTGT offers family testing and prenatal testing for all our genes.
•CTGT has a rapid turnaround time averaging about 2 weeks.
22
CONNECTIVE TISSUE GENE TESTS
MOLECULAR DIAGNOSIS
2 Test Requests:
1. Sequencing
2. Deletion/Duplication
23
CONNECTIVE TISSUE GENE TESTS
SEQUENCING
Probe: COL11A1 Gene
24
CONNECTIVE TISSUE GENE TESTS
SEQUENCING
COL11A1 Gene
The cat ran home.
The mat ran home.
25
CONNECTIVE TISSUE GENE TESTS
SEQUENCING
Result: COL11A1 IVS50+1G>A
Result: COL11A1 IVS50+1G>A
Test request:
Marshall syndrome COL11A1
Clinical Findings:
3 year old boy
Robin Sequence (cleft palate & small chin)
Flat face
Bilateral conductive hearing loss
26
Severe myopia (legally blind)
CONNECTIVE TISSUE GENE TESTS
DELETION/DUPLICATION
Test
Sample
Control
Sample
27
CONNECTIVE TISSUE GENE TESTS
DELETION/DUPLICATION
Clinical Findings:
2 year old boy
Flat face
Myopia at 15 months old
Short upturned nose
Cleft palate
Cleft palate
Flat face
Deletion/Duplication Results:
COL11A1 deletion exons 47-62
Sequencing Results:
COL2A1 sequencing negative
COL11A1 sequencing negative
COL11A2 sequencing negative
Deletion/Duplication Results:
COL2A1 deletion/duplication negative
COL11A1 deletion exons 47-62
28
CONNECTIVE TISSUE GENE TESTS
DELETION/DUPLICATION
COL11A1 gene no deletion
29
COL11A1 gene deletion of exons 47-62
CONNECTIVE TISSUE GENE TESTS
SEQUENCING VS.
DELETION/DUPLICATION
Sequencing-looks for small spelling errors in the gene’s set of
instructions.
Deletion/Duplication-looks for large sections of the
instructions that are missing.
30
CONNECTIVE TISSUE GENE TESTS
STICKLER SYNDROME TESTING
Gene
COL2A1
COL11A1
COL11A2
COL9A1
COL9A2
COL9A3
Sequencing
X
X
X
X
X
X
Deletion/Duplication
X
X
X
X
X
X
•CTGT offers both sequencing and deletion/duplication testing for all the
genes currently associated with Stickler syndrome.
•Having a genetic test is a choice not a requirement.
•Genetic testing is a personal decision and the decision is different for each
family and each person within a family.
31
THANK
YOU
Corrine Fillman, M.S., C.G.C.
Connective Tissue Gene Tests
(CTGT)
6580 Snowdrift Road, Suite 300
Allentown, PA 18106