Stickler syndrome (SS) is characterized by ophthalmic, articular, orofacial, and auditory manifestations. SS is usually autosomal dominantly inherited with variants in COL2A1 or COL11A1. Recessive forms are rare but have been described with homozygous variants in COL9A1, COL9A2, and COL9A3 and compound heterozygous COL11A1 variants. This article expands phenotypic descriptions in recessive SS due to variants in genes encoding Type IX collagen. Clinical features were assessed in four families. Genomic DNA samples derived from venous blood were collected from family members. Six affected patients were identified from four pedigrees with variants in COL9A1 (one family, one patient), COL9A2 (two families, three patients), and COL9A3 (one family, two patients). Three variants were novel. All patients were highly myopic with congenital megalophthalmos and abnormal, hypoplastic vitreous gel, and all had sensorineural hearing loss. One patient had severe arthropathy. Congenital megalophthalmos and myopia are common to dominant and recessive forms of SS. Sensorineural hearing loss is more common and severe in recessive SS. We suggest that COL9A1, COL9A2, and COL9A3 be added to genetic screening panels for patients with congenital hearing loss. Although recessive SS is rare, early diagnosis would have a high impact for children with potentially dual sensory impairment, as well as identifying risk to future children. K E Y W O R D S retina, retinal detachment, sensorineural hearing loss, Stickler, vitreoretinal

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1 , COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1 . Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.