title: Variants of anterior segment dysgenesis and cerebral involvement in a large family with a novel COL4A1 mutation.
abstract: OBJECTIVE
  To investigate the diverse ocular manifestations and identify the causative mutation in a large family with autosomal dominant anterior segment dysgenesis accompanied in some individuals by cerebral vascular disease.
  
  
  METHODS
  Retrospective observational case series and laboratory investigation.
  
  
  METHODS
  Forty-five family members from 4 generations underwent ophthalmic examination. Molecular genetic investigation included analysis with single nucleotide polymorphism (SNP) markers and DNA sequencing. Whole exome sequencing was performed in 1 individual.
  
  
  RESULTS
  A broad range of ocular manifestations was observed. Typical cases presented with corneal clouding, anterior synechiae, and iris hypoplasia. Posterior embryotoxon, corectopia, and early cataract development were also seen. One obligate carrier and several other family members had minor ocular anomalies, thus confounding the scoring of affected and unaffected individuals. Cerebral hemorrhages had occurred in 4 individuals, in 3 at birth or during the first year of life. Seven patients with corneal clouding were considered "definitely affected" for linkage studies. Haplotype mapping revealed that they shared a 14 cM region in the terminal part of chromosome 13q that included the locus for COL4A1. The affected family members were heterozygous for a novel COL4A1 sequence variant c.4881C>G (p.Asn1627Lys) predicted to be damaging and not found among 185 local blood donors. Exome sequencing showed that this variant was the only one in the candidate region not found in dbSNP.
  
  
  CONCLUSIONS
  Among the family members shown to carry the novel COL4A1 mutation, heterogenous presentations of anterior segment dysgenesis was seen. Testing family members for this mutation also made a definite diagnosis possible in patients with a clinical presentation difficult to classify. In families where anterior segment dysgenesis occurs together with cerebral hemorrhages, genetic analysis of COL4A1 should be considered.
authors: Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway. eyvind.rodahl@helse-bergen.no
authors: Eyvind
authors: E
authors: Rødahl
authors: Per M
authors: PM
authors: Knappskog
authors: Jacek
authors: J
authors: Majewski
authors: Stefan
authors: S
authors: Johansson
authors: Wenche
authors: W
authors: Telstad
authors: Jostein
authors: J
authors: Kråkenes
authors: Helge
authors: H
authors: Boman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000869:Anterior Eye Segment / Q000002:abnormalities*; D002561:Cerebrovascular Disorders / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D024141:Collagen Type IV / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV; D004247:DNA