Skeletal dysplasia

Gene: LOXL3

Green List (high evidence)

Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome. Skeletal findings included mild spondylo-epi-metaphyseal dysplasia in 1 case, and shortening of metacarpals and metatarsals in 3 sisters. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including skeletal dysplasia. As the skeletal findings are relatively mild, this gene should remain Amber on Skeletal dysplasia.

Created: 12 May 2026, 1:17 p.m. | Last Modified: 12 May 2026, 1:17 p.m.

Panel Version: 9.7

PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.

Created: 12 May 2026, 12:54 p.m. | Last Modified: 12 May 2026, 12:54 p.m.

Panel Version: 9.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354

Publications

• 25663169
• 30362103
• 36610533
• 36917121
• 38957076
• 41052910

Comment when marking as ready: Not ssociated with phenotype in OMIM nor G2P. One variant reported in biallelic Stickler syndrome

Created: 1 Aug 2016, 11:45 a.m.