title: 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.affiliation: Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: B
authors.initials: B
authors.lastname: Deml
authors.forename: L M
authors.initials: LM
authors.lastname: Reis
authors.forename: M
authors.initials: M
authors.lastname: Maheshwari
authors.forename: C
authors.initials: C
authors.lastname: Griffis
authors.forename: D
authors.initials: D
authors.lastname: Bick
authors.forename: E V
authors.initials: EV
authors.lastname: Semina
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000853:Anophthalmos / Q000235:genetics; D001483:Base Sequence; D002648:Child; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005123:Eye / Q000473:pathology*; D005190:Family; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007223:Infant; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV
keywords: COL4A1; Peters anomaly; microphthalmia; small vessel disease; stroke; whole exome sequencing