title: Nonsyndromic bilateral and unilateral optic nerve aplasia: first familial occurrence and potential implication of CYP26A1 and CYP26C1 genes.
abstract: OBJECTIVE
  Optic nerve aplasia (ONA, OMIM 165550) is a very rare unilateral or bilateral condition that leads to blindness in the affected eye, and is usually associated with other ocular abnormalities. Although bilateral ONA often occurs in association with severe congenital anomalies of the brain, nonsyndromic sporadic forms with bilateral ONA have been described. So far, no autosomal-dominant nonsyndromic ONA has been reported. The genetic basis of this condition remains largely unknown, as no developmental genes other than paired box gene 6 (PAX6) are known to be implicated in sporadic bilateral ONA.
  
  
  METHODS
  The individuals reported underwent extensive ophthalmological, endocrinological, and neurologic evaluation, including neuroimaging of the visual pathways. In addition genomewide copy number screening was performed.
  
  
  RESULTS
  Here we report an autosomal-dominant form of nonsyndromic ONA in a Belgian pedigree, with unilateral microphthalmia and ONA in the second generation (II:1), and bilateral ONA in two sibs of the third generation (III:1; III:2). No PAX6 mutation was found. Genome wide copy number screening revealed a microdeletion of maximal 363 kb of chromosome 10q23.33q23.33 in all affected individuals (II:1, III:1; III:2) and in unaffected I:1, containing three genes: exocyst complex component 6 (EXOC6), cytochrome p450, subfamily XXVIA, polypeptide 1 (CYP26A1), and cytochrome p450, subfamily XXVIC, polypeptide 1 (CYP26C1). The latter two encode retinoic acid-degrading enzymes.
  
  
  CONCLUSIONS
  This is the first study reporting an autosomal-dominant form of nonsyndromic ONA. The diagnostic value of neuroimaging in uncovering ONA in microphthalmic patients is demonstrated. Although involvement of other genetic factors cannot be ruled out, our study might point to a role of CYP26A1 and CYP26C1 in the pathogenesis of nonsyndromic ONA.
authors.affiliation: Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Meire
authors.forename: Isabelle
authors.initials: I
authors.lastname: Delpierre
authors.forename: Cecile
authors.initials: C
authors.lastname: Brachet
authors.forename: Françoise
authors.initials: F
authors.lastname: Roulez
authors.forename: Christian
authors.initials: C
authors.lastname: Van Nechel
authors.forename: Fanny
authors.initials: F
authors.lastname: Depasse
authors.forename: Catherine
authors.initials: C
authors.lastname: Christophe
authors.forename: Björn
authors.initials: B
authors.lastname: Menten
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
mesh_terms: D058070:Asymptomatic Diseases; D002675:Child, Preschool; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000737:chemistry / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072500:Cytochrome P450 Family 26; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D005799:Genes, Dominant; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008850:Microphthalmos / Q000235:genetics* / Q000503:physiopathology; D008875:Middle Aged; D009154:Mutation; D059906:Neuroimaging; D009900:Optic Nerve / Q000002:abnormalities / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism; D014787:Vision Tests
chemical_list: D005136:Eye Proteins; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C482075:CYP26C1 protein, human; D000072500:Cytochrome P450 Family 26; D000072516:Retinoic Acid 4-Hydroxylase