Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia.

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.

• Authors: B Deml, L M Reis, M Maheshwari, C Griffis, D Bick, E V Semina
• Journal: Clinical genetics (Clin Genet) Vol. 86 Issue 5 Pg. 475-81 (Nov 2014) ISSN: 1399-0004 [Electronic] Denmark
• PMID: 24628545 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• COL4A1 protein, human
• Collagen Type IV

Topics

• Adolescent
• Amino Acid Sequence
• Anophthalmos (genetics)
• Base Sequence
• Child
• Collagen Type IV (chemistry, genetics)
• DNA Mutational Analysis
• Exome (genetics)
• Eye (pathology)
• Family
• Female
• Genes, Dominant
• Humans
• Infant
• Male
• Microphthalmos (genetics)
• Molecular Sequence Data
• Mutation (genetics)
• Pedigree
• Phenotype