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Inherited and de novo biallelic pathogenic variants in COL11A1 result in type 2 Stickler syndrome with severe hearing loss.
Mol Genet Genomic Med. 2020 09; 8(9):e1354.MG

Abstract

BACKGROUND

Type 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly-Xaa-Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in-frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a COL11A1 related disorder, but here disease-associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy.

METHODS

The patient was assessed in the NHS England Stickler syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele-specific RT-PCR was performed.

RESULTS

This patient had clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of COL11A1 (c.4109_4126del) consistent with dominantly inherited Stickler syndrome but also a second inherited variant (c.1245+2T>C), on the other allele, affecting normal splicing of COL11A1 exon 9.

CONCLUSION

Exon 9 of COL11A1 is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic COL11A1 disease-associated variants and, instead of fibrochondrogenesis, produce a form of Stickler syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in COL11A1-related disorders, particularly for those variants that may alter normal pre-mRNA splicing.

Authors+Show Affiliations

School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. Vitreoretinal Service, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.Department of Pathology, University of Cambridge, Cambridge, UK. East Midlands and East of England NHS Genomic Laboratory Hub, Addenbrooke's Treatment Centre, Cambridge, UK.East Midlands and East of England NHS Genomic Laboratory Hub, Addenbrooke's Treatment Centre, Cambridge, UK.East Midlands and East of England NHS Genomic Laboratory Hub, Addenbrooke's Treatment Centre, Cambridge, UK.Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester, UK.Vitreoretinal Service, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Department of Pathology, University of Cambridge, Cambridge, UK.School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. Vitreoretinal Service, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. Vitreoretinal Service, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32578940

Citation

Nixon, Thomas, et al. "Inherited and De Novo Biallelic Pathogenic Variants in COL11A1 Result in Type 2 Stickler Syndrome With Severe Hearing Loss." Molecular Genetics & Genomic Medicine, vol. 8, no. 9, 2020, pp. e1354.
Nixon T, Richards AJ, Lomas A, et al. Inherited and de novo biallelic pathogenic variants in COL11A1 result in type 2 Stickler syndrome with severe hearing loss. Mol Genet Genomic Med. 2020;8(9):e1354.
Nixon, T., Richards, A. J., Lomas, A., Abbs, S., Vasudevan, P., McNinch, A., Alexander, P., & Snead, M. P. (2020). Inherited and de novo biallelic pathogenic variants in COL11A1 result in type 2 Stickler syndrome with severe hearing loss. Molecular Genetics & Genomic Medicine, 8(9), e1354. https://doi.org/10.1002/mgg3.1354
Nixon T, et al. Inherited and De Novo Biallelic Pathogenic Variants in COL11A1 Result in Type 2 Stickler Syndrome With Severe Hearing Loss. Mol Genet Genomic Med. 2020;8(9):e1354. PubMed PMID: 32578940.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inherited and de novo biallelic pathogenic variants in COL11A1 result in type 2 Stickler syndrome with severe hearing loss. AU - Nixon,Thomas, AU - Richards,Allan J, AU - Lomas,Adrian, AU - Abbs,Stephen, AU - Vasudevan,Pradeep, AU - McNinch,Annie, AU - Alexander,Philip, AU - Snead,Martin P, Y1 - 2020/06/24/ PY - 2020/03/10/received PY - 2020/04/27/revised PY - 2020/04/28/accepted PY - 2020/6/25/pubmed PY - 2021/5/21/medline PY - 2020/6/25/entrez KW - Stickler KW - retinal detachment KW - vitreoretinal SP - e1354 EP - e1354 JF - Molecular genetics & genomic medicine JO - Mol Genet Genomic Med VL - 8 IS - 9 N2 - BACKGROUND: Type 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly-Xaa-Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in-frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a COL11A1 related disorder, but here disease-associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy. METHODS: The patient was assessed in the NHS England Stickler syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele-specific RT-PCR was performed. RESULTS: This patient had clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of COL11A1 (c.4109_4126del) consistent with dominantly inherited Stickler syndrome but also a second inherited variant (c.1245+2T>C), on the other allele, affecting normal splicing of COL11A1 exon 9. CONCLUSION: Exon 9 of COL11A1 is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic COL11A1 disease-associated variants and, instead of fibrochondrogenesis, produce a form of Stickler syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in COL11A1-related disorders, particularly for those variants that may alter normal pre-mRNA splicing. SN - 2324-9269 UR - https://www.unboundmedicine.com/medline/citation/32578940/Inherited_and_de_novo_biallelic_pathogenic_variants_in_COL11A1_result_in_type_2_Stickler_syndrome_with_severe_hearing_loss_ L2 - https://doi.org/10.1002/mgg3.1354 DB - PRIME DP - Unbound Medicine ER -