Faculty Collaboration Database

Compound heterozygous splicing CDON variants result in isolated ocular coloboma. Clin Genet 2020 Nov;98(5):486-492

Date

07/31/2020

Pubmed ID

32729136

Pubmed Central ID

PMC8341436

DOI

10.1111/cge.13824

Scopus ID

2-s2.0-85089451171 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

Ocular coloboma is caused by failure of optic fissure closure during development and recognized as part of the microphthalmia, anophthalmia, and coloboma (MAC) spectrum. While many genes are known to cause colobomatous microphthalmia, relatively few have been reported in coloboma with normal eye size. Genetic analysis including trio exome sequencing and Sanger sequencing was undertaken in a family with two siblings affected with bilateral coloboma of the iris, retina, and choroid. Pathogenic variants in MAC genes were excluded. Trio analysis identified compound heterozygous donor splice site variants in CDON, a cell-surface receptor known to function in the Sonic Hedgehog pathway, c.928 + 1G > A and c.2650 + 1G > T, in both affected individuals. Heterozygous missense and truncating CDON variants are associated with dominant holoprosencephaly (HPE) with incomplete penetrance and Cdon-/- mice display variable HPE and coloboma. A homozygous nonsense allele of uncertain significance was recently identified in a consanguineous patient with coloboma and a second molecular diagnosis. We report the first compound heterozygous variants in CDON as a cause of isolated coloboma. CDON is the first HPE gene identified to cause recessive coloboma. Given the phenotypic overlap, further examination of HPE genes in coloboma is indicated.

Author List

Reis LM, Basel D, McCarrier J, Weinberg DV, Semina EV

Authors

Donald Basel MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Animals
Cell Adhesion Molecules
Coloboma
Eye
Female
Heterozygote
Holoprosencephaly
Humans
Male
Mice
Mutation
Protein Splicing
RNA Splicing
Tumor Suppressor Proteins
Young Adult