Knobloch syndrome (KS) is a rare autosomal recessive disorder characterized by eye abnormalities including high myopia, and usually accompanied by skull defects. COL18A1 that encodes a collagen is a known KS causing gene. Collagens are extracellular matrix (ECM) proteins. As the ECM is strongly implicated in the etiology of glaucoma, and as ocular anomalies are the defining features of KS pathology, it was considered that COL18A1 may affect glaucoma pathogenesis and that mutation carriers in KS families may be affected with glaucoma. Here, we describe clinical and genetic analysis of KS-unaffected individuals in two unrelated KS families.

Two young unrelated KS affected children were identified. Ophthalmic examinations and COL18A1 mutation screening were performed on the affected individuals. Upon identification of KS causing COL18A1 mutations, available members of the families underwent ophthalmic examinations and genetic analysis.

KS diagnosis was made and subsequently confirmed by genetic screening. Sequencing of COL18A1 resulted in identification of two novel homozygous deleterious mutations. Angle closure was diagnosed in four individuals of the six KS-unaffected members of the two families who underwent ophthalmic examination. Genetic screening results showed that all angle closure diagnosed individuals were heterozygous carriers of the COL18A1 mutations. Two mutation carriers had normal eye examination; these individuals were relatively young, aged between 35-45 yrs.

Diagnosis of angle closure in multiple individuals who are carriers of different mutations in COL18A1 supports the conjecture that mutations in this gene can promote this phenotype. This conjecture is further supported by known functions of collagens in the ECM. Concordance between angle closure and COL18A1 genotype was limited to older individuals which suggests that the phenotypic effects of mutations in COL18A1 with respect to angle closure are relatively late onset. Of course, other KS families need to be studied in order to definitively confirm these conclusions. We suspect that angle closure in parents of KS patients was not earlier reported because the condition had not yet become evident because the parents were young, or because the non-severe presentations of angle closure were overlooked in the framework of the more severe disease of offsprings.