Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2: a case report

Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2: a case report Ying Su, Chun-Qiong Ran, Zhe-Long Liu, Yan Yang, Gang Yuan, Shu-Hong Hu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2298863/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is ultra-rare, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few ballistic COL11A2 variants reported to date. Case presentation A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2 , both of which are predicted to be splicing mutations. One of the mutations is synonymous mutation c.3774C > T (p.Gly1258Gly) whereas it may cause splicing mutation predicted by in silico analysis, the other is a novel intron mutation c.4750 + 5 G > A which is a highly conservative site across several species. The patient received medications to alleviate the joint pain and osteoporosis. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS. Conclusion For patients with characteristic manifestations of SS syndrome, next-generation genetic analysis is beneficial for precision medical care and genetic counseling. type 3 Stickler syndrome COL11A2 splicing mutation case report Figures Figure 1 Figure 2 Figure 3 Introduction Stickler syndrome (SS) is a group of multisystem collagenopathies characterized by ophthalmic, auditory, craniofacial, articular and skeletal abnormalities. The first case of “hereditary progressive arthro-ophthalmopathy” was reported by Stickler et al dates back to 1965 [ 1 ] . SS is clinically and molecularly heterogeneous, which makes recognition and precise diagnosis of the disease difficult. Currently, pathogenic variants in six collagen-type genes ( COL2A1 , COL11A1 , COL11A2 , COL9A1 , COL9A2 and COL9A3 ) and at least 5 non-collagen genes ( LRP2 , GZF1 , BMP4 , PLOD3 and LOXL3 ) have been demonstrated to be involved in the pathogenesis of SS [ 2 – 7 ] . The abnormal modeling of the extracellular matrix in affected tissues caused by genetic mutations leads to characteristic manifestations in patients with SS. To date, it has been delineated that more than 40 different collagen genes are responsible for the synthesis and assembly of at least 29 types of collagen [ 8 ] . Nevertheless, the most causative genetic alterations in SS are found to be associated with abnormal production or assembly of fibrillar collagens II, IX and XI, which are found in the vitreous humor as well as hyaline and elastic cartilage [ 9 ] . Type 1 SS (OMIM #108300), accounting for 80–90% of cases, is featured by a high risk for blindness resulting from retinal detachment and membranous vitreous changes. The haploinsufficiency of COL2A1 , the encoding gene for collagen type II alpha 1 chain, is responsible for autosomal dominant type 1 SS [ 10 ] . Type 2 SS (OMIM #604841), representing the remaining 10–20% of cases, is usually caused by monoallelic mutations in COL11A1 which encodes the collagen type XI alpha 1 chain [ 11 ] . However, biallelic pathogenic variants of COL11A1 have also been reported occasionally [ 12 ] . Type 2 SS is characterized by a beaded vitreous phenotype, different from type 1 SS. Type 3 SS (OMIM #184840), is a rare form, previously known as non-ocular SS, or otospondylomegaepiphyseal dysplasia (OSMED) (OMIM #184840, #215150), or Weissenbacher Zweymüller syndrome. The first detailed description of this syndrome was made by pediatricians, Dr. Weissenbacher and Zweymüller, in 1964 [ 13 ] . The affected patient was a newborn of normal size, who had several signs of chondrodysplasia, including a markedly snub nose, coronal vertebral clefts, and rhizomelic shortness of limbs with dumb-bell-shaped femora [ 13 , 14 ] . The patient was free from ocular manifestations, such as myopia and vitreoretinal degeneration. The follow-up results of the original patient showed that he had developed sensorineural deafness at 5 years old, and spondyloepiphyseal dysplasia at about 13 years old [ 14 , 15 ] . After summarizing the common features of the four affected patients, Giedion et al . had postulated the nomenclature, OSMED, to better characterize this condition [ 15 ] . The identification of the pathogenic gene responsible for OSMED had been performed by directed sequencing of two candidate genes ( COL2A1 and COL11A2 ) expressed in cartilage [ 14 ] . Finally, COL11A2 mutation has been demonstrated to be the etiology of OSMED. Both autosomal dominant and recessive inheritable pattern of COL11A2 mutation have been documented to be involved in the pathogenesis of type 3 SS [ 16 , 17 ] , depending on the mutation sites. The uncommon causative genes for SS include coding genes for collagen IX protein, namely COL9A1 , COL9A2 and COL9A3 , together with non-collagen genes mentioned previously. In this report, we describe a 29-year-old Chinese male with non-ocular OSMED-like manifestations. Whole-exome sequencing of DNA from the peripheral blood has uncovered a composite heterozygous mutation of COL11A2 . We also review the currently known pathogenic mutations of COL11A2 for type 3 SS. Clinical Report A 29-year-old Chinese male was admitted to our hospital for recurrent pain in the low back, knee and ankle joints, which had troubled him for 2 years. He was from a non-consanguineous family. He had been born with normal weight and height. During his infancy, he was noted to have enlarged interphalangeal joints and O-shaped legs. Non-progressive hearing impairment occurred since his childhood, so his language development was retarded. His mental development seemed normal. No visual signs or symptoms had been observed. No similar symptoms occurred in his family members. On admission, he was 168 cm in height and 54.7 kg in weight (body mass index: 19.3 kg/m 2 ). Mild abnormal body proportions were observed, with a shorter upper part compared to the lower part (80 cm vs. 88 cm). In addition, his arm span was shorter than his height (160 cm vs. 168 cm). The patient had a snub nose, a high arched palate, micrognathia, and bilateral clinodactyly of the finger and toe joints. The ophthalmologic evaluation showed normal lens, vitreous, fundus and visual acuity. Bilateral sensorineural hearing loss was demonstrated by audiological examination. His middle and inner ear space appeared unremarkable with a magnetic resonance imaging (MRI) scan. Routine laboratory examinations were all negative, including erythrocyte sedimentation rate, complete blood cell count, antinuclear antibody, rheumatoid factor, thyroid hormone profiles and glucose metabolism. Body mass density (BMD) of the lumber spine and femur showed normal BMD and osteoporosis, respectively (Z-score: L1-4: -0.3, -0.5, 0, -0.2; femur: -2.5). The procollagen type 1 N-terminal prope-peptide (P1NP) was 83.2 ng/ml (9.06–76.24 ng/ml), and the carboxy-terminal cross-linked telopeptide of type 1 collagen (CTX) was 0.54 ng/ml (0.043–0.783 ng/ml). A radiographic examination revealed moderate to severe osteoarthritis in his metacarpophalangeal joints, wrists, knees and ankles. He also had various degrees of flattening of the vertebral bodies due to compression fracture (Fig. 1 ). Given the involvement of systematic chondroskeleton in the proband, we advised the performance of genetic diagnosis. After the consent of the patient and his family members, we employed high-throughput sequencing of the whole exome using DNA of the proband’s peripheral blood. It revealed that the proband harbored compound heterozygous mutations in COL11A2 . One is c.3774 C > T and the other is c.4750 + 5G > A (Fig. 2 A). The two mutations were confirmed by Sanger’s sequencing both in the proband and his parents. COL11A2 c.3774 C > T is located in a consensus sequence of 5’ splice site (Fig. 3 ). Therefore, we investigated the influence of this synonymous mutation on splicing process in silico (NetGene2, NNSPLICE0.9) (Table 1 ). These analyses suggested that c.3774 C > T may result in the aberrant 5’ splice site which was predominately used as a splice site. He was treated with bisphosphonates, calcium and Vitamin D to alleviate osteoporosis. The pains in multiple joints were treated with nonsteroidal anti-inflammatory drugs or gabapentin intermittently. Table 1 In silico splicing simulation of COL11A2 c.3774 C > T. Authentic 5' splice site Aberrant 5' splice site WT Mutant WT Mutant NetGene2 0 n.d n.d 0.7 NNSPLICE0.9 0.94 n.d 0.94 0.78 WT:Wild type; n.d: not detected. A score ranges between 0 and 1 for potential splice site, The higher the score, the higher the probability of variable splicing [ 29 ] . Discussion In this study, the patient was diagnosed with autosomal recessive type 3 SS based on clinical manifestations, imaging findings and genetic sequencing. As an uncommon cause of SS, type 3 SS is also known as non-ocular SS or OSMED. For the patient, one of the composite heterozygous mutations has been discovered in similar patients (c.3774C > T (p.Gly1258Gly) [ 18 ] , and the other is an intron mutation site that locates in a highly-conservative site across species (Fig. 2 B). Both mutations are supposed to cause abnormal splicing site mutations which affect the function of type XI collagen. Type XI collagen is a quantitatively minor component of collagen in cartilage, which co-polymerizes with type II and type IX collagen to form a heterotrimer. Type XI collagen is mainly composed of three types of chains, namely, α1 (XI), α2 (XI), and α3 (XI). COL11A2 is the coding gene for the α2 (XI) chain [ 19 ] . Hence, defects in COL11A2 will only affect osteoarthritis with normal ocular phenotype [ 20 ] . The mutation sites of the patient are both located in the triple helix region of collagen (Fig. 2 C), which is the sequence repetition of the amino acid triad -Gly-X-Y-. The majority of -X-Y- consists of prolines and hydroxyprolines that are essential for the formation and stabilization of the triple helix. The mutation sites in this region may lead to changes in the structure of the triple helix and corresponding functional changes [ 20 , 21 ] . Different clinical manifestations are caused by COL11A2 gene mutations depending on their types and sites. Missense mutations in the helix domain may destroy the stability of the helix structure. When they happen at the carboxyl end, the starting point of the collagen helical trimer, the corresponding clinical phenotype is the most serious. Frameshift or nonsense mutations do not result in disease phenotype in heterozygotes, whereas homozygotes exhibit autosomal recessive hereditary OSMED syndrome. Dominant non-ocular SS inheritance characterizes intra-frame deletion [ 22 ] . Synonymous mutations were previously thought to have no functional impact. Growing studies have shown that synonymous mutations affect DNA, RNA, and protein-based features [ 23 – 25 ] . The COL11A2 c.3774 C > T is close to the marginal zone of exons, which does not alter the protein sequence and may cause splicing abnormalities [ 26 ] . The other mutation site, c.4750 + 5G > A, is an intron mutation that has not previously been reported. Currently, it cannot be ruled out that deep intron mutations could result in disease [ 27 ] . Therefore, we investigated the influence of c.3774 C > T on the COL11A2 mRNA splicing process in silico (Table 1 ), which resulted in aberrant splicing via the aberrant 5’ splice site (Fig. 3 ). The proband’s parents both are asymptomatic with a heterozygous mutation. Over the past 20 years, a taxonomy of the SS subgroups based on vitreous characteristics has emerged. It has been shown that this taxonomy is a reliable strategy for both diagnosing SS and directing molecular study [ 11 , 12 ] . Type 3 SS is a non-ocular type of SS, manifesting as prelingual development of sensorineural hearing loss, growth of the epiphyses with generalized shortening of the limbs, and vertebral body dysplasia. Characteristic facial characteristics include an upturned nose, a low nasal bridge, and midface hypoplasia. The condition appears radiographically to impact numerous joints. The upper and lower extremity's long bones are frequently seen to be shorter, with extensive epiphyses and metaphyseal flare that give them a dumbbell form. The coronal clefts in the spine's vertebral bodies indicate faulty ossification, making the vertebral bodies platyspondyly. Despite having shorter stature as children, most patients grow to be about average height. Patients typically experience joint discomfort due to prevalent arthritic changes. Clinically, the possibility of type 3 SS should be considered in patients with early sensorineural deafness, skeletal abnormalities, and imaging changes. Genetic detection should be carried out as soon as possible to determine the cause. At present, there is no efficient treatment for SS. Individualized treatment seems appropriate according to the different symptoms and signs. Early-stage surgical repair of skeletal abnormalities in children with type 3 SS has been reported in the past, and the short-term outcome is favorable. However, as age increases and the disease symptoms worsen, the surgical correction becomes more challenging, and the worse the prognosis [ 28 ] . There are several limitations to our case report. First of all, we did not perform any additional functional testing. It still needs to be established whether the synonymous mutation in this patient leads to alternative splicing. Secondly, due to the paucity of clinical awareness of the disease, the patient had spent a lot of time on disease diagnosis. SS should be considered when patients exhibit typical deafness, bone abnormalities, and other features. In the end, although the patient has type 3 SS, there is currently no effective treatment. However, the validation of the causative gene is beneficial for genetic counseling. In conclusion, we report a rare case of autosomal recessive type 3 SS. Both intronic and synonymous mutations are easily missed by conventional whole exome sequencing. Next-generation whole genome sequencing, in silico prediction, and possibly supplementary functional analysis are warranted for the accurate diagnosis of these patients. Abbreviations SS: Stickler syndrome; COL11A2: collagen alpha-2(XI) chain; OSMED: otospondylomegaepiphyseal dysplasia; COL2A1: collagen alpha-1(II) chain; COL11A1: collagen alpha-1(XI) chain; COL9A1: collagen alpha-1(IX) chain; COL9A2: collagen alpha-2(IX) chain; COL9A3: collagen alpha-3(IX); LRP2: low-density lipoprotein receptor-related protein 2; GZF1: GDNF-inducible zinc finger protein 1; BMP4: bone morphogenetic protein 4; PLOD3: multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3; LOXL3: lysyl oxidase homolog 3; MRI: magnetic resonance imaging; BMD: body mass density; P1NP: procollagen type 1 N-terminal prope-peptide; CTX: carboxy-terminal cross-linked telopeptide of type 1 collagen. Declarations Acknowledgements We are grateful to the patient and his family members. Funding This study was supported by China Diabetes Excellence Study (2018-N-01) of China International Medical Exchange Foundation. Availability of data and materials All data generated or analyzed in this study are included in this manuscript. Authors’ contributions YS conceived the experiment and prepared the manuscript. CQR and ZLL performed the gene sequencing and genetic counselling. YY, GY, SHH, XFY and WTH guided the performance of the study. Ethics approval and consent to participate Written informed consent was obtained from the patient and his family members. This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. All methods were performed in accordance with the relevant guidelines and regulations. Consent for publication Written informed consent for publication of medical data and genetic data was obtained from all family members. Competing interests The authors declare that they have no competing interests. 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Zeng Z, Aptekmann AA, Bromberg Y: Decoding the effects of synonymous variants. NUCLEIC ACIDS RES. 2021; 49(22):12673-12691. Vuoristo MM, Pappas JG, Jansen V, Ala-Kokko L: A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome. AM J MED GENET A. 2004; 130A(2):160-164. Wu H, Che S, Li S, Cheng Y, Xiao J, Liu Z: Case report of the first molecular diagnosis of Stickler syndrome with a pathogenic COL2A1 variant in a Mongolia family. MOL GENET GENOM MED. 2021; 9(10):e1781. Snead MP, Richards AJ, McNinch AM, Alexander P, Martin H, Nixon T, Bale P, Shenker N, Brown S, Blackwell AM et al: Stickler syndrome - lessons from a national cohort. EYE. 2022; 36(10):1966-1972. Williams BR, Calhoun A, Holton KJ, Kelly BJ, Sembrano JN: Otospondylomegaepiphyseal Dysplasia: A Case Report of Clinical and Radiographic Findings. JBJS Case Connect. 2020; 10(4):e20-e140. Jian X, Boerwinkle E, Liu X: In silico prediction of splice-altering single nucleotide variants in the human genome. NUCLEIC ACIDS RES. 2014; 42(22):13534-13544. Additional Declarations No competing interests reported. Supplementary Files CAREchecklist.pdf TableS1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2298863","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":156532496,"identity":"5b381323-0f9b-44a9-9c18-d8a3241f72bc","order_by":0,"name":"Ying Su","email":"","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Su","suffix":""},{"id":156532497,"identity":"62ef38d0-896b-4d9f-9e80-58b255547ad3","order_by":1,"name":"Chun-Qiong Ran","email":"","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chun-Qiong","middleName":"","lastName":"Ran","suffix":""},{"id":156532498,"identity":"11da514f-4e84-47bf-93ce-a2353dbbc54e","order_by":2,"name":"Zhe-Long Liu","email":"","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhe-Long","middleName":"","lastName":"Liu","suffix":""},{"id":156532499,"identity":"616ddc3f-7bec-465b-b9aa-5848564175f5","order_by":3,"name":"Yan Yang","email":"","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Yang","suffix":""},{"id":156532500,"identity":"875a35a4-5e7b-4676-a2bf-8b271df5ccc9","order_by":4,"name":"Gang Yuan","email":"","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gang","middleName":"","lastName":"Yuan","suffix":""},{"id":156532501,"identity":"31c3be49-47a0-4ec1-85c2-b1b31695d10c","order_by":5,"name":"Shu-Hong Hu","email":"","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shu-Hong","middleName":"","lastName":"Hu","suffix":""},{"id":156532502,"identity":"a82d14fe-04eb-4e05-b0f5-03473a5b844a","order_by":6,"name":"Xue-Feng Yu","email":"","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xue-Feng","middleName":"","lastName":"Yu","suffix":""},{"id":156532503,"identity":"8851fc9d-2c96-47a4-af5e-66d9e1ed3ace","order_by":7,"name":"Wen-Tao He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYFACHgaGDwxsCUAWCDMwNhDUwcbDwDgjAaiFjRQtzDwJDCAtDMRpMbjfe/Cx7Q++PAb5hqebeRhsZDccYH72AK+WY3zJxjkJbMVAW9Ju8zCkGW84wGZugE+L2TEeM2mglsQGiJbDiRsO8LBJENBi/tsCoeU/UVrMmBkQWg4Q1mJ/LMdYsieNLbGNLSHt5hyDZOOZh9nM8GqRbD5j+OGHzbHEfuYzaTfeVNjJ9h1vfoZXCxQcAwYYMHYYQEHFTIR6IKgBYvYDxKkdBaNgFIyCEQcApS1EQcwuWwcAAAAASUVORK5CYII=","orcid":"","institution":"Branch of National Clinical Research Center for Metabolic Disease, Huazhong University of Science and Technology","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Wen-Tao","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2022-11-22 00:44:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2298863/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2298863/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":29909752,"identity":"48eab55f-ded1-4160-96da-7f20d41cc51f","added_by":"auto","created_at":"2022-12-05 15:27:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2199132,"visible":true,"origin":"","legend":"\u003cp\u003eThe radiological findings of osteoarthritis in the proband. (A) Radiographs of the knees, ankles, left hand and foot, showing the diffuse joint-space-narrowing. (B) Radiographs and magnetic resonance of the spine, showing platyspondyly.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2298863/v1/eb4c791886aeb93a3646a05d.png"},{"id":29911065,"identity":"36027d0d-f302-4f2a-8c43-51da2f6fad3a","added_by":"auto","created_at":"2022-12-05 15:35:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":71773,"visible":true,"origin":"","legend":"\u003cp\u003ePedigrees of the proband and the genetic characteristics of the pedigree. (A) Pedigrees of the proband (arrow indicates proband). (B) The Sanger sequencing of the family and the evolutionary conservation of the cluster across multiple species. (C) \u003cem\u003eCOL11A2\u003c/em\u003e variants associated with type 3 SS, variants were collected from ClinVar and previously reported (variants written in black), the pathogenic variant in the proband is marked in red (the suspected splicing mutation \u003cem\u003eCOL11A2\u003c/em\u003e c.4750+5G \u0026gt; A is not shown) (\u003ca href=\"https://legacy.uniprot.org/uniprot/P13942\"\u003ehttps://legacy.uniprot.org/uniprot/P13942\u003c/a\u003e).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2298863/v1/59c202c247eb821cb4213580.png"},{"id":29909753,"identity":"579167df-0f09-45a6-a17f-242c15b1613c","added_by":"auto","created_at":"2022-12-05 15:27:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":48002,"visible":true,"origin":"","legend":"\u003cp\u003eA proposed model for the role of the \u003cem\u003eCOL11A2 \u003c/em\u003ec.3774C＞T mutation. The red C represents the mutation site.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-2298863/v1/a498dcf28a1b9717c8c22000.png"},{"id":31742301,"identity":"cc193e6f-7a6f-4159-835e-6b478e4f7372","added_by":"auto","created_at":"2023-01-18 11:44:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1911268,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2298863/v1/e79d0243-95c6-4e94-bdfc-179b572a1eda.pdf"},{"id":29909756,"identity":"d736cefe-05f3-441e-8dd9-0157a31a963a","added_by":"auto","created_at":"2022-12-05 15:27:21","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":784990,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2298863/v1/8ef31b3a8e29366701cdf3a1.pdf"},{"id":29909755,"identity":"03afeee4-c39d-468c-9c68-4059fbc0417b","added_by":"auto","created_at":"2022-12-05 15:27:21","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":11724,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2298863/v1/ca02750a7629e6258551eda6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2: a case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eStickler syndrome (SS) is a group of multisystem collagenopathies characterized by ophthalmic, auditory, craniofacial, articular and skeletal abnormalities. The first case of \u0026ldquo;hereditary progressive arthro-ophthalmopathy\u0026rdquo; was reported by Stickler \u003cem\u003eet al\u003c/em\u003e dates back to 1965\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. SS is clinically and molecularly heterogeneous, which makes recognition and precise diagnosis of the disease difficult. Currently, pathogenic variants in six collagen-type genes (\u003cem\u003eCOL2A1\u003c/em\u003e, \u003cem\u003eCOL11A1\u003c/em\u003e, \u003cem\u003eCOL11A2\u003c/em\u003e, \u003cem\u003eCOL9A1\u003c/em\u003e, \u003cem\u003eCOL9A2\u003c/em\u003e and \u003cem\u003eCOL9A3\u003c/em\u003e) and at least 5 non-collagen genes (\u003cem\u003eLRP2\u003c/em\u003e, \u003cem\u003eGZF1\u003c/em\u003e, \u003cem\u003eBMP4\u003c/em\u003e, \u003cem\u003ePLOD3\u003c/em\u003e and \u003cem\u003eLOXL3\u003c/em\u003e) have been demonstrated to be involved in the pathogenesis of SS\u003csup\u003e[\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. The abnormal modeling of the extracellular matrix in affected tissues caused by genetic mutations leads to characteristic manifestations in patients with SS. To date, it has been delineated that more than 40 different collagen genes are responsible for the synthesis and assembly of at least 29 types of collagen\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, the most causative genetic alterations in SS are found to be associated with abnormal production or assembly of fibrillar collagens II, IX and XI, which are found in the vitreous humor as well as hyaline and elastic cartilage\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eType 1 SS (OMIM #108300), accounting for 80\u0026ndash;90% of cases, is featured by a high risk for blindness resulting from retinal detachment and membranous vitreous changes. The haploinsufficiency of \u003cem\u003eCOL2A1\u003c/em\u003e, the encoding gene for collagen type II alpha 1 chain, is responsible for autosomal dominant type 1 SS\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eType 2 SS (OMIM #604841), representing the remaining 10\u0026ndash;20% of cases, is usually caused by monoallelic mutations in \u003cem\u003eCOL11A1\u003c/em\u003e which encodes the collagen type XI alpha 1 chain\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. However, biallelic pathogenic variants of \u003cem\u003eCOL11A1\u003c/em\u003e have also been reported occasionally\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Type 2 SS is characterized by a beaded vitreous phenotype, different from type 1 SS.\u003c/p\u003e \u003cp\u003eType 3 SS (OMIM #184840), is a rare form, previously known as non-ocular SS, or otospondylomegaepiphyseal dysplasia (OSMED) (OMIM #184840, #215150), or Weissenbacher Zweym\u0026uuml;ller syndrome. The first detailed description of this syndrome was made by pediatricians, Dr. Weissenbacher and Zweym\u0026uuml;ller, in 1964\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. The affected patient was a newborn of normal size, who had several signs of chondrodysplasia, including a markedly snub nose, coronal vertebral clefts, and rhizomelic shortness of limbs with dumb-bell-shaped femora\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. The patient was free from ocular manifestations, such as myopia and vitreoretinal degeneration. The follow-up results of the original patient showed that he had developed sensorineural deafness at 5 years old, and spondyloepiphyseal dysplasia at about 13 years old \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. After summarizing the common features of the four affected patients, Giedion \u003cem\u003eet al\u003c/em\u003e. had postulated the nomenclature, OSMED, to better characterize this condition\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. The identification of the pathogenic gene responsible for OSMED had been performed by directed sequencing of two candidate genes (\u003cem\u003eCOL2A1\u003c/em\u003e and \u003cem\u003eCOL11A2\u003c/em\u003e) expressed in cartilage\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Finally, \u003cem\u003eCOL11A2\u003c/em\u003e mutation has been demonstrated to be the etiology of OSMED. Both autosomal dominant and recessive inheritable pattern of \u003cem\u003eCOL11A2\u003c/em\u003e mutation have been documented to be involved in the pathogenesis of type 3 SS\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, depending on the mutation sites.\u003c/p\u003e \u003cp\u003eThe uncommon causative genes for SS include coding genes for collagen IX protein, namely \u003cem\u003eCOL9A1\u003c/em\u003e, \u003cem\u003eCOL9A2\u003c/em\u003e and \u003cem\u003eCOL9A3\u003c/em\u003e, together with non-collagen genes mentioned previously.\u003c/p\u003e \u003cp\u003eIn this report, we describe a 29-year-old Chinese male with non-ocular OSMED-like manifestations. Whole-exome sequencing of DNA from the peripheral blood has uncovered a composite heterozygous mutation of \u003cem\u003eCOL11A2\u003c/em\u003e. We also review the currently known pathogenic mutations of \u003cem\u003eCOL11A2\u003c/em\u003e for type 3 SS.\u003c/p\u003e "},{"header":"Clinical Report","content":"\u003cdiv class=\"Section2\" id=\"Sec2\"\u003e\n \u003cp\u003eA 29-year-old Chinese male was admitted to our hospital for recurrent pain in the low back, knee and ankle joints, which had troubled him for 2 years. He was from a non-consanguineous family. He had been born with normal weight and height. During his infancy, he was noted to have enlarged interphalangeal joints and O-shaped legs. Non-progressive hearing impairment occurred since his childhood, so his language development was retarded. His mental development seemed normal. No visual signs or symptoms had been observed. No similar symptoms occurred in his family members. On admission, he was 168 cm in height and 54.7 kg in weight (body mass index: 19.3 kg/m\u003csup\u003e2\u003c/sup\u003e). Mild abnormal body proportions were observed, with a shorter upper part compared to the lower part (80 cm vs. 88 cm). In addition, his arm span was shorter than his height (160 cm vs. 168 cm). The patient had a snub nose, a high arched palate, micrognathia, and bilateral clinodactyly of the finger and toe joints. The ophthalmologic evaluation showed normal lens, vitreous, fundus and visual acuity. Bilateral sensorineural hearing loss was demonstrated by audiological examination. His middle and inner ear space appeared unremarkable with a magnetic resonance imaging (MRI) scan. Routine laboratory examinations were all negative, including erythrocyte sedimentation rate, complete blood cell count, antinuclear antibody, rheumatoid factor, thyroid hormone profiles and glucose metabolism. Body mass density (BMD) of the lumber spine and femur showed normal BMD and osteoporosis, respectively (Z-score: L1-4: -0.3, -0.5, 0, -0.2; femur: -2.5). The procollagen type 1 N-terminal prope-peptide (P1NP) was 83.2 ng/ml (9.06\u0026ndash;76.24 ng/ml), and the carboxy-terminal cross-linked telopeptide of type 1 collagen (CTX) was 0.54 ng/ml (0.043\u0026ndash;0.783 ng/ml). A radiographic examination revealed moderate to severe osteoarthritis in his metacarpophalangeal joints, wrists, knees and ankles. He also had various degrees of flattening of the vertebral bodies due to compression fracture (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Given the involvement of systematic chondroskeleton in the proband, we advised the performance of genetic diagnosis. After the consent of the patient and his family members, we employed high-throughput sequencing of the whole exome using DNA of the proband\u0026rsquo;s peripheral blood. It revealed that the proband harbored compound heterozygous mutations in \u003cem\u003eCOL11A2\u003c/em\u003e. One is c.3774 C\u0026thinsp;\u0026gt;\u0026thinsp;T and the other is c.4750\u0026thinsp;+\u0026thinsp;5G\u0026thinsp;\u0026gt;\u0026thinsp;A (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The two mutations were confirmed by Sanger\u0026rsquo;s sequencing both in the proband and his parents. \u003cem\u003eCOL11A2\u003c/em\u003e c.3774 C\u0026thinsp;\u0026gt;\u0026thinsp;T is located in a consensus sequence of 5\u0026rsquo; splice site (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Therefore, we investigated the influence of this synonymous mutation on splicing process \u003cem\u003ein silico\u003c/em\u003e (NetGene2, NNSPLICE0.9) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). These analyses suggested that c.3774 C\u0026thinsp;\u0026gt;\u0026thinsp;T may result in the aberrant 5\u0026rsquo; splice site which was predominately used as a splice site. He was treated with bisphosphonates, calcium and Vitamin D to alleviate osteoporosis. The pains in multiple joints were treated with nonsteroidal anti-inflammatory drugs or gabapentin intermittently.\u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cem\u003eIn silico\u003c/em\u003e splicing simulation of \u003cem\u003eCOL11A2\u003c/em\u003e c.3774 C\u0026thinsp;\u0026gt;\u0026thinsp;T.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" style=\"width: 12.3387%;\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\" style=\"width: 19.4136%;\"\u003e\n \u003cp\u003eAuthentic 5\u0026apos; splice site\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\" style=\"width: 19.0174%;\"\u003e\n \u003cp\u003eAberrant 5\u0026apos; splice site\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 12.3387%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.4711%;\"\u003e\n \u003cp\u003eWT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.8859%;\"\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.3579%;\"\u003e\n \u003cp\u003eWT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6595%;\"\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 12.3387%;\"\u003e\n \u003cp\u003eNetGene2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.4711%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.8859%;\"\u003e\n \u003cp\u003en.d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.3579%;\"\u003e\n \u003cp\u003en.d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6595%;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 12.3387%;\"\u003e\n \u003cp\u003eNNSPLICE0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.4711%;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.8859%;\"\u003e\n \u003cp\u003en.d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 7.3579%;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 11.6595%;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\" style=\"width: 51.7319%;\"\u003e\n \u003cp\u003eWT:Wild type; n.d: not detected. A score ranges between 0 and 1 for potential splice site, The higher the score, the higher the probability of variable splicing\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, the patient was diagnosed with autosomal recessive type 3 SS based on clinical manifestations, imaging findings and genetic sequencing. As an uncommon cause of SS, type 3 SS is also known as non-ocular SS or OSMED. For the patient, one of the composite heterozygous mutations has been discovered in similar patients (c.3774C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Gly1258Gly)\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, and the other is an intron mutation site that locates in a highly-conservative site across species (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Both mutations are supposed to cause abnormal splicing site mutations which affect the function of type XI collagen.\u003c/p\u003e \u003cp\u003eType XI collagen is a quantitatively minor component of collagen in cartilage, which co-polymerizes with type II and type IX collagen to form a heterotrimer. Type XI collagen is mainly composed of three types of chains, namely, α1 (XI), α2 (XI), and α3 (XI). \u003cem\u003eCOL11A2\u003c/em\u003e is the coding gene for the α2 (XI) chain\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Hence, defects in \u003cem\u003eCOL11A2\u003c/em\u003e will only affect osteoarthritis with normal ocular phenotype\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe mutation sites of the patient are both located in the triple helix region of collagen (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), which is the sequence repetition of the amino acid triad -Gly-X-Y-. The majority of -X-Y- consists of prolines and hydroxyprolines that are essential for the formation and stabilization of the triple helix. The mutation sites in this region may lead to changes in the structure of the triple helix and corresponding functional changes\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDifferent clinical manifestations are caused by \u003cem\u003eCOL11A2\u003c/em\u003e gene mutations depending on their types and sites. Missense mutations in the helix domain may destroy the stability of the helix structure. When they happen at the carboxyl end, the starting point of the collagen helical trimer, the corresponding clinical phenotype is the most serious. Frameshift or nonsense mutations do not result in disease phenotype in heterozygotes, whereas homozygotes exhibit autosomal recessive hereditary OSMED syndrome. Dominant non-ocular SS inheritance characterizes intra-frame deletion\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Synonymous mutations were previously thought to have no functional impact. Growing studies have shown that synonymous mutations affect DNA, RNA, and protein-based features\u003csup\u003e[\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. The \u003cem\u003eCOL11A2\u003c/em\u003e c.3774 C\u0026thinsp;\u0026gt;\u0026thinsp;T is close to the marginal zone of exons, which does not alter the protein sequence and may cause splicing abnormalities \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. The other mutation site, c.4750\u0026thinsp;+\u0026thinsp;5G\u0026thinsp;\u0026gt;\u0026thinsp;A, is an intron mutation that has not previously been reported. Currently, it cannot be ruled out that deep intron mutations could result in disease\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Therefore, we investigated the influence of c.3774 C\u0026thinsp;\u0026gt;\u0026thinsp;T on the \u003cem\u003eCOL11A2\u003c/em\u003e mRNA splicing process \u003cem\u003ein silico\u003c/em\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), which resulted in aberrant splicing via the aberrant 5\u0026rsquo; splice site (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The proband\u0026rsquo;s parents both are asymptomatic with a heterozygous mutation.\u003c/p\u003e \u003cp\u003eOver the past 20 years, a taxonomy of the SS subgroups based on vitreous characteristics has emerged. It has been shown that this taxonomy is a reliable strategy for both diagnosing SS and directing molecular study\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Type 3 SS is a non-ocular type of SS, manifesting as prelingual development of sensorineural hearing loss, growth of the epiphyses with generalized shortening of the limbs, and vertebral body dysplasia. Characteristic facial characteristics include an upturned nose, a low nasal bridge, and midface hypoplasia. The condition appears radiographically to impact numerous joints. The upper and lower extremity's long bones are frequently seen to be shorter, with extensive epiphyses and metaphyseal flare that give them a dumbbell form. The coronal clefts in the spine's vertebral bodies indicate faulty ossification, making the vertebral bodies platyspondyly. Despite having shorter stature as children, most patients grow to be about average height. Patients typically experience joint discomfort due to prevalent arthritic changes. Clinically, the possibility of type 3 SS should be considered in patients with early sensorineural deafness, skeletal abnormalities, and imaging changes. Genetic detection should be carried out as soon as possible to determine the cause.\u003c/p\u003e \u003cp\u003eAt present, there is no efficient treatment for SS. Individualized treatment seems appropriate according to the different symptoms and signs. Early-stage surgical repair of skeletal abnormalities in children with type 3 SS has been reported in the past, and the short-term outcome is favorable. However, as age increases and the disease symptoms worsen, the surgical correction becomes more challenging, and the worse the prognosis\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere are several limitations to our case report. First of all, we did not perform any additional functional testing. It still needs to be established whether the synonymous mutation in this patient leads to alternative splicing. Secondly, due to the paucity of clinical awareness of the disease, the patient had spent a lot of time on disease diagnosis. SS should be considered when patients exhibit typical deafness, bone abnormalities, and other features. In the end, although the patient has type 3 SS, there is currently no effective treatment. However, the validation of the causative gene is beneficial for genetic counseling.\u003c/p\u003e \u003cp\u003eIn conclusion, we report a rare case of autosomal recessive type 3 SS. Both intronic and synonymous mutations are easily missed by conventional whole exome sequencing. Next-generation whole genome sequencing, \u003cem\u003ein silico\u003c/em\u003e prediction, and possibly supplementary functional analysis are warranted for the accurate diagnosis of these patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSS: Stickler syndrome; COL11A2: collagen alpha-2(XI) chain; OSMED: otospondylomegaepiphyseal dysplasia; COL2A1: collagen alpha-1(II) chain; COL11A1: collagen alpha-1(XI) chain; COL9A1: collagen alpha-1(IX) chain; COL9A2: collagen alpha-2(IX) chain; COL9A3: collagen alpha-3(IX); LRP2: low-density lipoprotein receptor-related protein 2; GZF1: GDNF-inducible zinc finger protein 1; BMP4: bone morphogenetic protein 4; PLOD3: multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3; LOXL3: lysyl oxidase homolog 3; MRI: magnetic resonance imaging; BMD: body mass density; P1NP: procollagen type 1 N-terminal prope-peptide; CTX: carboxy-terminal cross-linked telopeptide of type 1 collagen.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the patient and his family members.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by China Diabetes Excellence Study (2018-N-01) of China International Medical Exchange Foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed in this study are included in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYS conceived the experiment and prepared the manuscript. CQR and ZLL performed the gene sequencing and genetic counselling. YY, GY, SHH, XFY and WTH guided the performance of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient and his family members. This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. All methods were performed in accordance with the relevant guidelines and regulations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of medical data and genetic data was obtained from all family members.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSTICKLER GB, BELAU PG, FARRELL FJ, JONES JD, PUGH DG, STEINBERG AG, WARD LE: HEREDITARY PROGRESSIVE ARTHRO-OPHTHALMOPATHY. MAYO CLIN PROC.\u0026nbsp;1965;\u0026nbsp;40:433-455.\u003c/li\u003e\n \u003cli\u003eChan TK, Alkaabi MK, ElBarky AM, El-Hattab AW: LOXL3 novel mutation causing a rare form of autosomal recessive Stickler syndrome. 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PROG RETIN EYE RES.\u0026nbsp;2004;\u0026nbsp;23(4):403-434.\u003c/li\u003e\n \u003cli\u003eRoche PA, Cresswell P: Proteolysis of the class II-associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules. Proc. Natl. Acad. Sci. USA. 1991;\u0026nbsp;88: 3150-3154. J IMMUNOL 2011, 187(3):1076-1080.\u003c/li\u003e\n \u003cli\u003eSoh Z, Richards AJ, McNinch A, Alexander P, Martin H, Snead MP: Dominant Stickler Syndrome. GENES-BASEL.\u0026nbsp;2022;\u0026nbsp;13(6).\u003c/li\u003e\n \u003cli\u003eNixon T, Richards AJ, Martin H, Alexander P, Snead MP: Autosomal Recessive Stickler Syndrome. GENES-BASEL.\u0026nbsp;2022;\u0026nbsp;13(7).\u003c/li\u003e\n \u003cli\u003eWEISSENBACHER G, ZWEYMUELLER E: [SIMULTANEOUS OCCURRANCE OF THE PIERRE ROBIN SYNDROME AND FETAL CHONDRODYSPLASIA]. Monatsschr Kinderheilkd (1902).\u0026nbsp;1964;\u0026nbsp;112:315-317.\u003c/li\u003e\n \u003cli\u003ePihlajamaa T, Prockop DJ, Faber J, Winterpacht A, Zabel B, Giedion A, Wiesbauer P, Spranger J, Ala-Kokko L: Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymuller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). Am J Med Genet.\u0026nbsp;1998;\u0026nbsp;80(2):115-120.\u003c/li\u003e\n \u003cli\u003eGiedion A, Brandner M, Lecannellier J, Muhar U, Prader A, Sulzer J, Zweymuller E: Oto-spondylo-megaepiphyseal dysplasia (OSMED). Helv Paediatr Acta.\u0026nbsp;1982;\u0026nbsp;37(4):361-380.\u003c/li\u003e\n \u003cli\u003eVikkula M, Mariman EC, Lui VC, Zhidkova NI, Tiller GE, Goldring MB, van Beersum SE, de Waal MM, van den Hoogen FH, Ropers HH et al: Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. CELL.\u0026nbsp;1995;\u0026nbsp;80(3):431-437.\u003c/li\u003e\n \u003cli\u003eMelkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kaariainen H, Pauli RM, van Essen T, Warman ML, Bonaventure J et al: Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. AM J HUM GENET.\u0026nbsp;2000;\u0026nbsp;66(2):368-377.\u003c/li\u003e\n \u003cli\u003eAcke FR, Malfait F, Vanakker OM, Steyaert W, De Leeneer K, Mortier G, Dhooge I, De Paepe A, De Leenheer EM, Coucke PJ: Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing. MOL GENET METAB.\u0026nbsp;2014;\u0026nbsp;113(3):230-235.\u003c/li\u003e\n \u003cli\u003eBruckner P, van der Rest M: Structure and function of cartilage collagens. MICROSC RES TECHNIQ.\u0026nbsp;1994;\u0026nbsp;28(5):378-384.\u003c/li\u003e\n \u003cli\u003eSnead MP, McNinch AM, Poulson AV, Bearcroft P, Silverman B, Gomersall P, Parfect V, Richards AJ: Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. EYE.\u0026nbsp;2011;\u0026nbsp;25(11):1389-1400.\u003c/li\u003e\n \u003cli\u003eChakchouk I, Grati M, Bademci G, Bensaid M, Ma Q, Chakroun A, Foster JN, Yan D, Duman D, Diaz-Horta O et al: Novel mutations confirm that COL11A2 is responsible for autosomal recessive non-syndromic hearing loss DFNB53. MOL GENET GENOMICS.\u0026nbsp;2015;\u0026nbsp;290(4):1327-1334.\u003c/li\u003e\n \u003cli\u003eChen W, Kahrizi K, Meyer NC, Riazalhosseini Y, Van Camp G, Najmabadi H, Smith RJ: Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the \u0026nbsp;DFNB53 locus. J MED GENET 2005, 42(10):e61.\u003c/li\u003e\n \u003cli\u003eHunt RC, Simhadri VL, Iandoli M, Sauna ZE, Kimchi-Sarfaty C: Exposing synonymous mutations. TRENDS GENET.\u0026nbsp;2014;\u0026nbsp;30(7):308-321.\u003c/li\u003e\n \u003cli\u003eZeng Z, Aptekmann AA, Bromberg Y: Decoding the effects of synonymous variants. NUCLEIC ACIDS RES.\u0026nbsp;2021;\u0026nbsp;49(22):12673-12691.\u003c/li\u003e\n \u003cli\u003eVuoristo MM, Pappas JG, Jansen V, Ala-Kokko L: A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome. AM J MED GENET A.\u0026nbsp;2004;\u0026nbsp;130A(2):160-164.\u003c/li\u003e\n \u003cli\u003eWu H, Che S, Li S, Cheng Y, Xiao J, Liu Z: Case report of the first molecular diagnosis of Stickler syndrome with a pathogenic COL2A1 variant in a Mongolia family. MOL GENET GENOM MED.\u0026nbsp;2021;\u0026nbsp;9(10):e1781.\u003c/li\u003e\n \u003cli\u003eSnead MP, Richards AJ, McNinch AM, Alexander P, Martin H, Nixon T, Bale P, Shenker N, Brown S, Blackwell AM et al: Stickler syndrome - lessons from a national cohort. EYE.\u0026nbsp;2022;\u0026nbsp;36(10):1966-1972.\u003c/li\u003e\n \u003cli\u003eWilliams BR, Calhoun A, Holton KJ, Kelly BJ, Sembrano JN: Otospondylomegaepiphyseal Dysplasia: A Case Report of Clinical and Radiographic Findings. JBJS Case Connect.\u0026nbsp;2020;\u0026nbsp;10(4):e20-e140.\u003c/li\u003e\n \u003cli\u003eJian X, Boerwinkle E, Liu X: In silico prediction of splice-altering single nucleotide variants in the human genome. NUCLEIC ACIDS RES. 2014; 42(22):13534-13544.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"type 3 Stickler syndrome, COL11A2, splicing mutation, case report","lastPublishedDoi":"10.21203/rs.3.rs-2298863/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2298863/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\n\u003cp\u003eStickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is ultra-rare, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few ballistic \u003cem\u003eCOL11A2\u003c/em\u003e variants reported to date.\u003c/p\u003e\n\u003ch2\u003eCase presentation\u003c/h2\u003e\n\u003cp\u003eA 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in \u003cem\u003eCOL11A2\u003c/em\u003e, both of which are predicted to be splicing mutations. One of the mutations is synonymous mutation c.3774C \u0026gt; T (p.Gly1258Gly) whereas it may cause splicing mutation predicted by \u003cem\u003ein silico\u003c/em\u003e analysis, the other is a novel intron mutation c.4750 + 5 G \u0026gt; A which is a highly conservative site across several species. The patient received medications to alleviate the joint pain and osteoporosis. We also present a review of the current known pathogenic mutation spectrum of \u003cem\u003eCOL11A2\u003c/em\u003e in patients with type 3 SS.\u003c/p\u003e\n\u003ch2\u003eConclusion\u003c/h2\u003e\n\u003cp\u003eFor patients with characteristic manifestations of SS syndrome, next-generation genetic analysis is beneficial for precision medical care and genetic counseling.\u003c/p\u003e","manuscriptTitle":"Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-05 15:27:16","doi":"10.21203/rs.3.rs-2298863/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2a20ff1-cb2c-438f-92f5-1f738626f526","owner":[],"postedDate":"December 5th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-18T11:44:17+00:00","versionOfRecord":[],"versionCreatedAt":"2022-12-05 15:27:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2298863","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2298863","identity":"rs-2298863","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}