Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications

Ewans, LJ; Colley, A; Gaston-Massuet, C; Gualtieri, A; Cowley, MJ; McCabe, MJ; Anand, D; Lachke, SA; Scietti, L; Forneris, F; Zhu, Y; Ying, K; Walsh, C; Kirk, EP; Miller, D; Giunta, C; Sillence, D; DInger, M; Buckley, M; Roscioli, T

Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications

Ewans, LJ Colley, A Gaston-Massuet, C Gualtieri, A Cowley, MJ McCabe, MJ Anand, D Lachke, SA Scietti, L Forneris, F Zhu, Y Ying, K

Walsh, C Kirk, EP Miller, D Giunta, C Sillence, D DInger, M Buckley, M Roscioli, T

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Publication Type:: Journal Article
Citation:: Journal of Medical Genetics, 2019, 56 (9), pp. 629 - 638
Issue Date:: 2019-09-01

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Field	Value	Language
dc.contributor.author	Ewans, LJ	en_US
dc.contributor.author	Colley, A	en_US
dc.contributor.author	Gaston-Massuet, C	en_US
dc.contributor.author	Gualtieri, A	en_US
dc.contributor.author	Cowley, MJ	en_US
dc.contributor.author	McCabe, MJ	en_US
dc.contributor.author	Anand, D	en_US
dc.contributor.author	Lachke, SA	en_US
dc.contributor.author	Scietti, L	en_US
dc.contributor.author	Forneris, F	en_US
dc.contributor.author	Zhu, Y	en_US
dc.contributor.author	Ying, K https://orcid.org/0000-0001-6041-8773	en_US
dc.contributor.author	Walsh, C	en_US
dc.contributor.author	Kirk, EP	en_US
dc.contributor.author	Miller, D	en_US
dc.contributor.author	Giunta, C	en_US
dc.contributor.author	Sillence, D	en_US
dc.contributor.author	DInger, M	en_US
dc.contributor.author	Buckley, M	en_US
dc.contributor.author	Roscioli, T	en_US
dc.date.available	2019-04-25	en_US
dc.date.issued	2019-09-01	en_US
dc.identifier.citation	Journal of Medical Genetics, 2019, 56 (9), pp. 629 - 638	en_US
dc.identifier.issn	0022-2593	en_US
dc.identifier.uri	http://hdl.handle.net/10453/136203
dc.description.abstract	© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Background Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease. Methods Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. Results Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. Conclusion These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.	en_US
dc.relation.ispartof	Journal of Medical Genetics	en_US
dc.relation.isbasedon	10.1136/jmedgenet-2019-106019	en_US
dc.subject.classification	Genetics & Heredity	en_US
dc.title	Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications	en_US
dc.type	Journal Article
utslib.citation.volume	9	en_US
utslib.citation.volume	56	en_US
utslib.for	0604 Genetics	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
pubs.issue	9	en_US
pubs.publication-status	Published	en_US
pubs.volume	56	en_US

Abstract:

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Background Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease. Methods Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. Results Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. Conclusion These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

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http://hdl.handle.net/10453/136203