Abstract
BACKGROUND/OBJECTIVES: Knobloch syndrome 1 (KS) is an autosomal recessive inherited ocular syndrome characterized by a combination of high myopia, vitreoretinal degeneration, and occipital encephalocele. KS is caused by biallelic pathogenic variants in the COL18A1 gene. Diagnosing KS can be challenging due to its clinical heterogeneity and the rarity of the syndrome. METHODS: We conducted comprehensive clinical and instrumental ophthalmological examinations, whole-exome sequencing, Sanger sequencing, and segregation analysis to evaluate affected families. RESULTS: Two patients presenting with high myopia, low visual acuity, chorioretinal atrophy, and occipital skin/skull defects were diagnosed with Knobloch syndrome 1 (KS). In Case 1, a 14-year-old boy, the COL18A1 variants identified were c.2673dup and c.3523_3524del in a compound heterozygous state. Case 2 involved a 3-year-old girl, the c.1637_1638dup and c.3523_3524del variants were identified in a compound heterozygous state. In Case 3, a retrospectively observed boy of 3 y.o. with KS, the variants c.929-2A>G and c.3523_3524del were defined earlier. CONCLUSIONS: We confirmed KS molecularly in two novel families. Additionally, in Case 3 of a retrospectively analyzed third family and in both novel cases, one of the biallelic causative variants was the same known 2bp deletion in exon 40 of the collagen XVIII gene. Cases 1 and 3 were characterized by connective tissue dysplasia features and a pathognomonic Knobloch triad. No neurological manifestations and no trends in the genotype-phenotype relationship were found. The heterogeneity of phenotype in the case series is likely to be the result of further factors and/or genetic background.