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Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications
  1. Lisa Jean Ewans1,2,
  2. Alison Colley3,
  3. Carles Gaston-Massuet4,
  4. Angelica Gualtieri4,
  5. Mark J Cowley1,2,
  6. Mark James McCabe1,2,
  7. Deepti Anand5,
  8. Salil A Lachke5,6,
  9. Luigi Scietti7,
  10. Federico Forneris7,
  11. Ying Zhu8,9,
  12. Kevin Ying2,
  13. Corrina Walsh9,
  14. Edwin P Kirk9,10,
  15. David Miller2,
  16. Cecilia Giunta11,
  17. David Sillence12,
  18. Marcel Dinger2,13,
  19. Michael Buckley9,
  20. Tony Roscioli9,14
  1. 1 St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia
  2. 2 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
  3. 3 Clinical Genetics Department, Liverpool Hospital, Liverpool, New South Wales, Australia
  4. 4 Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, UK
  5. 5 Department of Biological Sciences, University of Delaware, Newark, Delaware, USA
  6. 6 Center for Bioinformatics and Computational Biology, University of Delaware, Newark, Delaware, USA
  7. 7 Department of Biology and Biotechnology, Universita degli Studi di Pavia, Pavia, Lombardia, Italy
  8. 8 Newcastle GOLD Service, Hunter Genetics, Waratah, New South Wales, Australia
  9. 9 NSW Health Pathology East Laboratory, Prince of Wales Private Hospital, Randwick, New South Wales, Australia
  10. 10 School of Women’s and Children’s Health, University of New South Wales, Randwick, New South Wales, Australia
  11. 11 Connective Tissue Unit, Division of Metabolism, University Children’s Hospital Zurich, Zurich, Switzerland
  12. 12 Genomic Medicine, University of Sydney, Sydney, New South Wales, Australia
  13. 13 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington Campus, Sydney, New South Wales, Australia
  14. 14 Neuroscience Research Australia, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia
  1. Correspondence to Dr Lisa Jean Ewans, St Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia; lisa.ewans{at}


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.

  • LH3
  • PLOD3
  • tissue expression
  • connective tissue disorder
  • stickler syndrome

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  • Correction notice This article has been corrected since it was published Online First. The name of author

    Salil A Lachke has been corrected.

  • Contributors LJE is the primary author; identified PLOD3 variant in family presented from whole exome sequencing data, collation of clinical information and description, analysis of clinical presentations, analysis of CTD features and comparison with individuals with PLOD3-related disease, primary drafting and review of manuscript, tables, figures, contact and coordination of collaborating authors. AC is the lead clinician involved in this family’s management; coordinated urine sample collections, DNA, consents, collation of clinical information and description, review of drafts. CG-M is the lead contributing author on PLOD3/LH3 human embryonic tissue expression including generation, analysis, supervision and interpretation of this novel work, drafting of manuscript. AG contributed to the PLOD3/LH3 human embryonic tissue expression including generation, analysis and interpretation of this novel work, figure generation. MJC is the lead on whole exome sequencing bioinformatics, assistance with drafting of manuscript. MJMcC provided assistance with PLOD3/LH3 human embryonic tissue expression including collaboration connection, drafting of manuscript. DA and SL contributed to heat map/mouse microarray expression work for CTDs. LS and FF contributed to the computational evaluation of PLOD3 variant using LH3 crystal structures. YZ provided assistance with variant filtering and prioritisation methodology. KY provided assistance with whole exome sequencing bioinformatics. CW contributed to the supervision of laboratory work with regard to Sanger sequencing segregation in family. EPK helped with the clinical report writing and interpretation of PLOD3 variant and manuscript review. DM supervised the whole exome sequencing wet lab/methodology. CG helped with urinary pyridinoline crosslink work including generation and interpretation of data and manuscript review. DS was involved in family clinically in paediatric setting, additional clinical information curation, manuscript review and expertise in CTD. MED contributed to supervision of primary author and genomic sequencing laboratory tools/equipment/resources. MB supervised clinical laboratory tools/interpretation/equipment/resources. TR contributed to supervision of primary author including variant interpretation, supervision and introduction with some collaborating authors, assistance with direction of work, drafting and review of manuscript.

  • Funding Action Medical Research: GN2272 Early Career Fellowship; Associazione Italiana per la Ricerca sul Cancro: MFAG 20075; Giovanni Armenise-Harvard Foundation: Career Development Award 2013; Medical Research Council: 099175; Ministero dell’Istruzione, dell’Universita e della Ricerca: Dipartimenti di; Eccellenza Program 2018-2022.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the ethics committee at the Prince of Wales Hospital Campus, Sydney, Australia (HREC ref no. 13/094).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are available in a public, open access repository.