Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree

Abstract

Aim: To explore the clinical feature and genetic etiology of a Chinese Knobloch syndrome family.

Methods: Ocular examinations and magnetic resonance imagings (MRIs) were performed on the family. Whole exome sequencing was conducted on the two patients. Sanger sequencing was utilized to validate the presence of variation in the family as well as in 100 normal controls. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression level of COL18A1 in peripheral blood lymphocytes of the patients and normal carriers.

Results: The affected subjects presented with vision loss, exotropia, cataracts, retinal detachment, and other complications. A homozygous c.4759_4760delCT (p.Leu1587ValfsX72) mutation (rs398122391) in COL18A1 was identified in the two patients, cosegregating with the phenotypes, and did not be detected in 100 normal controls. This mutation caused significant decreased expression of COL18A1 mRNA in the patients.

Conclusion: The findings strongly indicate that this mutation is the disease-causing mutation. Moreover, this is the first Knobloch syndrome pedigree reported in the Chinese population.

Keywords: COL18A1; Knobloch syndrome; whole exome sequencing.

Figure 1. Ocular phenotypes of patients II:2 and II:3

A: The Chinese Knobloch syndrome pedigree. Roman numerals referred to generations, and individuals within a generation were numbered from left to right, as per convention. Proband was noted with arrow, and died proband was noted with slash line. Filled symbol referred to the patient. Open symbol referred unaffected individual; B: A total cataract complicated with lens subluxation in the right eye of II:2; C: A myopic fundus with myopic macular scarring in the left eye of II:2; D, E: Fundus examination showed high myopic fundus in both eyes of II:3.

Figure 2. Sanger sequencing validation and RNA expression of the mutation COL18A1 c.4759_4760delCT in the Chinese Knobloch syndrome pedigree

A: The figure shows the DNA sequence of COL18A1 in the Chinese autosomal recessive pedigree and normal control. The arrow referred to mutant base; B: mRNA expression of COL18A1 in lymphocytes of affected individuals, carriers, and controls. Mean expression (±SEM) of COL18A1 in affected individuals (n=2), carriers (n=2), and controls (n=3) measured by quantitive real-time PCR. ^aP<0.0001.