Compound heterozygous splicing CDON variants result in isolated ocular coloboma

Area of Science:

• Genetics
• Developmental Biology
• Ophthalmology

Background:

• Ocular coloboma, part of the microphthalmia, anophthalmia, and coloboma (MAC) spectrum, results from optic fissure closure failure.
• While numerous genes cause colobomatous microphthalmia, few are linked to coloboma with normal eye size.

Purpose of the Study:

• To investigate the genetic cause of isolated bilateral ocular coloboma in a family with two affected siblings.
• To identify novel genetic factors contributing to the MAC spectrum, particularly in cases without microphthalmia.

Main Methods:

• Trio exome sequencing and Sanger sequencing were performed on affected siblings and their parents.
• Exclusion of known pathogenic variants in established MAC genes.
• Analysis focused on identifying novel variants, particularly in genes involved in developmental pathways.

Main Results:

• Compound heterozygous splice site variants (c.928+1G>A and c.2650+1G>T) in the CDON gene were identified in both affected siblings.
• These variants were absent in unaffected family members.
• CDON, a Sonic Hedgehog pathway receptor, was previously linked to dominant holoprosencephaly (HPE).

Conclusions:

• This study reports the first instance of compound heterozygous CDON variants causing isolated ocular coloboma, establishing a recessive inheritance pattern.
• CDON is identified as the first HPE gene implicated in recessive coloboma.
• The findings suggest a need for further investigation of HPE-related genes in patients with coloboma due to phenotypic overlap.