1. Genetics of Stickler Syndrome
Noralane M. Lindor, M.D. Department of Medical Genetics Mayo Clinic, Rochester, Minnesota

2. Stickler, G. B. et al. , Hereditary progressive arthro-ophthalmopathy
Stickler, G. B.et al., Hereditary progressive arthro-ophthalmopathy. Mayo Clin. Proc. 40: , 1965.
…from a long experience at the Mayo Clinic with multiple members of a kindred, described a new dominant entity consisting of progressive myopia beginning in the first decade of life and resulting in retinal detachment and blindness. Affected persons also exhibited premature degenerative changes in various joints with abnormal epiphyseal development and slight hypermobility in some.
From On Line Mendelian Inheritance
in Man (OMIM) 2007

3. Stickler Syndrome Genetic disorder of connective tissue
Due to mutation in one of several genes that encode different types of collagen proteins that are important ingredients of connective tissue of the eye, ear, cartilage, and other tissues.

4. Construction of a body part
Bricks
Mortar
Cells
“Connective tissue”

5. What is mortar? Recipe of multiple ingredients
What is connective tissue?
Recipe of multiple ingredients
Elastin
Fibrillin
Collagens
Tissue growth factors
Etc, etc, etc

6. Where does connective tissue come from? How is it made?
Secreted by the cells themselves based on the genetic instructions within those cells

7. Stickler Syndrome A clinical diagnosis–
i.e., diagnosis does not depend on genetic mutation being found
Note: mutations in the genes causative of some cases of Stickler Syndrome can also cause other syndromes that are not Stickler Syndrome

8. Stickler Syndrome:consider dx if have findings in >2 categories
Eye: congenital/early onset cataract, congenital vitreous anomaly, rhegmatogenous retinal detachment, myopia >-3 diopters
Craniofacial: midface hypoplasia, bifid uvula, cleft palate, micrognathia
Ear: sensorineural or conductive hearing loss, hypermobility of middle ear structures
Joints: hypermobility, spondyloepiphyseal dysplasia, early onset osteoarthritis

9. Edited Slide Clinical variability of Stickler syndrome
Courtesy of: Journal of Med Genetics

10. Metaphase spread of chromosomes from one cell

11. Organization of human chromosomes into a “karyotype”
46,XY

12. 30,000 genes lined up single file along the chromosomes

13. Chromosome 19
hundreds to
thousands of
different genes
on each
chromosome

14. Name and address of the 4 genes associated with Stickler Syndrome
COL2A1 chromosome 12q13
COL11A1 chromosome 1p21
COL11A2 chromosome 6p21.3
COL9A1 chromosome 6q13

15. Stickler Syndrome gene locations
COL11A1
COL11A2
COL2A1
COL9A1

16. Individual collagen molecule is a triple helix
Repetitve sequence Gly-X-Y where X and Y are frequently proline. It forms a three-stranded triple helix

17. Edited Slide Variation in the Vitreous Phenotype of Stickler Syndrome
Can Be Caused by Different Amino
Acid Substitutions in the X Position
of the Type II Collagen Gly-X-Y
Triple Helix Variation in the
VitreousPhenotype of Stickler
Syndrome Can Be Caused by
Different Amino Acid Substitutions
in the X Position of the Type II
Collagen Gly-X-Y Triple Helix
COL2A1 exon 2 Mutations
American Journal of Human Genetics

18. Collagen genes vs collagen fibers
40 different genes encoding at least 27 different types of collagens
22 different collagens seen in embryonic or mature eye
Only 6 different collagens seen in eye are also present in joint cartilage. These include Type II, V/XI, VI, IX, and XXVII.
Best candidate genes for Stickler syndrome

19. Collagen Type II
Type II Collagen made up of three chains of collagen encoded by COL2A1
Causes Stickler Syndrome Type 1
The most common type
Eye finding most often persistence of vestigial vitreous gel in retrolental space, border by folded membrane, “membranous”

20. Collagen Type XI
Type XI Collagen is made up of three different strands encoded by:
COL2A1
COL11A1
COL11A2
Mutations in COL11A1 cause Stickler Syndrome type II
COL11A2 causes non ocular Stickler Syndrome or Stickler Syndrome Type III

21. Genotype:Phenotype
Mutations in COL11A1 have typical Stickler eye findings– usually a beaded pattern vitreopathy (rarely membranous)
“alpha 1 chain”
COL11A2 not expressed in vitreous (COL5A2 chain replaces it in Type XI Collagen) therefore no eye problems in Type II Stickler with COL11A2 mutations
“alpha 2 chain”

22. Collagen Type IX
Type IX Collagen composed of one strand each encoded by three different genes:
COL9A1
COL9A2
COL9A3
Mutations in COL9A1 can cause autosomal recessive Stickler Syndrome– Type IV??

23. Stickler Syndrome gene locations
COL11A1
COL11A2
COL2A1
COL9A1 +

24. Stickler Syndrome Types I and II: Autosomal Dominant
50-50 chance of passing gene to child
Does not matter if parent or child is male or female

25. Stickler Syndrome due to COL9A1: autosomal recessive
Both parents carry one gene mutation but do not have Stickler 25% probability of each child having Stickler Syndrome
Child who inherits mutated gene from both mother and father have Stickler Syndrome

26. First case in family: recessive or de novo dominant mutation?

27. Putting all the genetics together

28. Genetic testing available, moderately sensitive
COL2A1 27-80% mutations found
COL11A1 50-80%
COL11A2 unknown but available
COL9A1 unknown and unavailable
BUT……….!

29. Finding gene mutation not equal to diagnosis of Stickler Syndrome
Mutations in COL2A1 also cause:
Achondrogenesis type II
Hypochondrogenesis
Spondyloepiphyseal dysplasia congenita
Spondyloepimetaphyseal dysplasia Studwick type
Kneist dysplasia
Spondyloperipheral dysplasia
Early-onset arthropathy
AD rhegmatogenous retinal detachment

30. Chondroectodermal dysplasia

31. “Allelic disorder”: same gene, different disorder
Different types of disruption/mutation of a gene affects the collagen production in different ways
The clinical picture may vary a lot
Within a family, relatives have the same disorder because they have the same mutation, but severity can be quite variable.

32. Furthermore….
Mutations in COL11A1 can cause Marshall Syndrome– hypoplasia of midface and nasal bones and sinuses, myopia, cataracts, deafness, short stature, early arthritis, decreases hair and sweating
Allelic or different disorder?

33. Furthermore…. Mutations in COL11A2 can cause
Autosomal recessive otospondylometaepiphyseal dysplasia
Weissenback-Zweymuller Syndrome
Nonsyndromic sensorineural hearing loss

34. Furthermore…..
Mutations in COL9A1 can cause a multiple epiphyseal dysplasia: short trunked short stature, multiple joints abnormal

35. Multiple epiphyseal dysplasia (MED)
– mild short stature, irregularity of
multiple epiphyses, early arthritis
Genetic heterogeneity: about 10%
Due to mutations in COL9 genes
From European Journal of Human
Genetics (2007) 15, 150–154.

36. Stickler Syndrome Genetic Testing – a choice, not a requirement
Medically helpful? Would it tell
more than the family history?
Diagnosis correct?
Risk for eye complications?
Reproductive risks: 50%? 25%? <1%?
Prenatal diagnosis?
Psychologically – do you want/need to know?
Cost? Insurance issues….