title: Novel mutations in PAX6, OTX2 and NDP in anophthalmia, microphthalmia and coloboma.
abstract: Anophthalmia and microphthalmia (A/M) are developmental ocular malformations defined as the complete absence or reduction in size of the eye. A/M is a highly heterogeneous disorder with SOX2 and FOXE3 playing major roles in dominant and recessive pedigrees, respectively; however, the majority of cases lack a genetic etiology. We analyzed 28 probands affected with A/M spectrum (without mutations in SOX2/FOXE3) by whole-exome sequencing. Analysis of 83 known A/M factors identified pathogenic/likely pathogenic variants in PAX6, OTX2 and NDP in three patients. A novel heterozygous likely pathogenic variant in PAX6, c.767T>C, p.(Val256Ala), was identified in two brothers with bilateral microphthalmia, coloboma, primary aphakia, iris hypoplasia, sclerocornea and congenital glaucoma; the unaffected mother appears to be a mosaic carrier. While A/M has been reported as a rare feature, this is the first report of congenital primary aphakia in association with PAX6 and the identified allele represents the first variant in the PAX6 homeodomain to be associated with A/M. A novel pathogenic variant in OTX2, c.651delC, p.(Thr218Hisfs*76), in a patient with syndromic bilateral anophthalmia and a hemizygous pathogenic variant in NDP, c.293 C>T, p.(Pro98Leu), in two brothers with isolated bilateral microphthalmia and sclerocornea were also identified. Pathogenic/likely pathogenic variants were not discovered in the 25 remaining A/M cases. This study underscores the utility of whole-exome sequencing for identification of causative mutations in highly variable ocular phenotypes as well as the extreme genetic heterogeneity of A/M conditions.
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, WI, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Deml
authors.affiliation: Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Reis
authors.affiliation: Service de Génétique médicale, CHU Ste-Justine, Département de Pédiatrie, Université de Montréal, Montréal, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lemyre
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Loma Linda University Children's Hospital, Loma Linda, CA 92354.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clark
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
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, WI, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Semina
mesh_terms: D000293:Adolescent; D000328:Adult; D000853:Anophthalmos / Q000235:genetics*; D002648:Child; D003103:Coloboma / Q000235:genetics*; D059472:Exome; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051857:Otx Transcription Factors / Q000235:genetics*; D000071841:PAX6 Transcription Factor / Q000235:genetics*
chemical_list: D005136:Eye Proteins; C081848:NDP protein, human; D009419:Nerve Tissue Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human