Stickler syndrome (STL) is a rare, clinically and genetically heterogeneous connective tissue disorder divided into six clinical subtypes with overlapping features, including ocular pathologies (myopia, retinal detachment, vitreoretinal degeneration, cataract), hearing impairment (sensorineural, mixed, and/or conductive), craniofacial abnormalities (midface hypoplasia, anteverted nares, depressed nasal bridge and either Pierre Robin sequence or cleft palate and micrognathia) and joint problems (mild spondyloepiphyseal dysplasia, and precocious osteoarthritis) (1). These features exhibit substantial variable expressivity according to clinical subtype (1). STL is molecularly diagnosed by the presence of pathogenic variants in six collagen-type genes including COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3, and two non-collagen genes consisting of LRP2 and LOXL3 (1-3), following a predominantly autosomal dominant inheritance pattern.
The heteropolymer collagen XI/IX/II are critical in the extracellular matrix of joints, bones, ligaments and connective tissues throughout the body (4). COL2A1 encodes collagen type II alpha 1 chain. Heterozygous variants that cause functional haploinsufficiency are responsible for autosomal dominant STL type I (OMIM #108300), representing the most common subtype, accounting for roughly 80-90% of STL (5, 6). Pathogenic variants in COL11A1 cause the second most common STL subtype, type II (OMIM #604841) (10-20%). Variants in this gene likewise typically follow a dominant inheritance pattern (7), although five families have been described with STL and biallelic COL11A1 mutations (8-10). COL11A2 pathogenic variants are very rare and cause autosomal dominant non-ocular Stickler syndrome (type III, OMIM#184840), also known as otospondylomegaepiphyseal dysplasia (OSMEDA, OMIM# 120290), as well as Weissenbacher-Zweymuller syndrome (WZS) (OMIM #184840) (11). Biallelic variants in LOXL3, a member of the lysyl oxidase family of genes, have recently been causally associated with STL in two unrelated families (2, 12). A biallelic missense variant in LRP2 has likewise been suggested to cause STL (3).
Collagen IX proteins are encoded by COL9A1, COL9A2 and COL9A3 that together form fibril heterotrimer associated collagens and have been recently linked to autosomal recessive STL (13). Multiple epiphyseal dysplasia (MED) is an autosomal dominant allelic disorder caused by mutations in any of these three genes (1). Very recently, heterozygous COL9A3 variants have been identified as causing peripheral vitreoretinal degeneration and retinal detachment (14). COL9A1 and COL9A2 are causally associated with autosomal recessive STL type IV (OMIM #614134) and V (OMIM #614284), respectively. The main clinical characteristics of individuals affected with biallelic COL9A1 variants include moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia, whereas COL9A2 variants are associated with high myopia, vitreoretinal degeneration, retinal detachment, hearing loss, and short stature. Only very recently, biallelic mutations in COL9A3 have been described to cause autosomal recessive STL in four unrelated families with seven patients (13, 15-17). The main phenotypes that are common in all these patients consisted of high myopia, moderate to severe sensorineural hearing loss, and spondylo/epiphyseal dysplasia. Here, we report three additional unrelated consanguineous STL families with five affected individuals in total who each present three novel biallelic COL9A3 variants.