Novel COL9A1 mutation causes autosomal recessive isolated high myopia

Background/Objectives: Identifying the genetic cause of isolated high myopia affecting two siblings in consanguineous Bedouin family.
Methods: Affected individuals underwent thorough ophthalmologic examination, including fundus photography and optical coherence tomography (OCT). Whole-exome sequencing (WES) of the proband and homozygosity mapping of the studied kindred (750k SNP arrays) were done, assuming autosomal recessive heredity. WES variants which passed our filtering cascade were screened using our database of 500 ethnically-matched controls and validated using Sanger sequencing.
Results: The two siblings were affected since infancy, and recently, ages 18 and 21 years, their refractive errors ranged from -8 to -20 dioptres. One sibling had anisometropia (9 dioptres), amblyopia, and strabismus. Fundus and OCT findings were compatible with high myopia. They had no facial deformities, hearing loss or skeletal anomalies. Linkage analysis unravelled several homozygous loci shared only by two affected individuals. Using our variant analysis pipeline, all WES variants within these loci were ruled out except for one: COL9A1 (NM_001851.4): c.1550G>A, p.G517E, segregating in the kindred as expected for recessive heredity and not found in 500 ethnically-matched controls or public databases.
Conclusion: We report a novel COL9A1 mutation causing autosomal recessive high myopia without systemic abnormalities. COL9A1 takes part in assembly of type IX collagen molecules, and is expressed in various tissues including the eye. COL9A1 mutations were previously reported mainly in association with Stickler syndrome, hearing loss and multiple epiphyseal dysplasia. Our findings suggest that genetic evaluation of isolated severe myopia should include analysis for the presence of COL9A1 pathogenic variants.