Pathogenic variants in <i>PLOD3</i> result in a Stickler syndrome-like connective tissue disorder with vascular complications.

Abstract

Pathogenic <i>PLOD3</i> 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 <i>PLOD3</i>-related disease. Reported <i>PLOD3</i> phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous <i>PLOD3</i> 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. 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/<i>PLOD3</i> expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. These data are consistent with pathogenic variants in <i>PLOD3</i> resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of <i>PLOD3</i> variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.