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

Stickler, G. B. et al. , Hereditary progressive arthro-ophthalmopathy Stickler, G. B.et al., Hereditary progressive arthro-ophthalmopathy. Mayo Clin. Proc. 40: 433-455, 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

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.

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

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

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

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

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

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

Metaphase spread of chromosomes from one cell

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

30,000 genes lined up single file along the chromosomes

Chromosome 19 hundreds to thousands of different genes on each chromosome

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

Stickler Syndrome gene locations COL11A1 COL11A2 COL2A1 COL9A1

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

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

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

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”

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

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”

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??

Stickler Syndrome gene locations COL11A1 COL11A2 COL2A1 COL9A1 +

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

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

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

Putting all the genetics together

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

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

Chondroectodermal dysplasia

“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.

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?

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

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

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.

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….