Faculty Collaboration Database

Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. Clin Genet 2014 Nov;86(5):475-81

Date

03/19/2014

Pubmed ID

24628545

Pubmed Central ID

PMC4163542

DOI

10.1111/cge.12379

Scopus ID

2-s2.0-84911978460 (requires institutional sign-in at Scopus site)   39 Citations

Abstract

Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogenous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain magnetic resonance imaging (MRI) in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of 24 unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern.

Author List

Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina EV

Authors

Mohit Maheshwari MD Professor in the Radiology 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
Amino Acid Sequence
Anophthalmos
Base Sequence
Child
Collagen Type IV
DNA Mutational Analysis
Exome
Eye
Family
Female
Genes, Dominant
Humans
Infant
Male
Microphthalmos
Molecular Sequence Data
Mutation
Pedigree
Phenotype