title: Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia.
abstract: To investigate the genetic etiology of anophthalmia and microphthalmia, we used exome sequencing in a Caucasian female with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, ventricular and atrial septal defects, and growth delays. We found two sequence variants in SALL4 - c.[575C>A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G>C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency for SALL4 due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities. Our report is the first description of structural eye defects associated with two missense variants in SALL4 inherited in trans; the absence of reported findings in both parents suggests that both sequence variants are hypomorphic mutations and that both are needed for the ocular phenotype. SALL4 is expressed in the developing lens and regulates BMP4, leading us to speculate that altered BMP4 expression was responsible for the eye defects, but we could not demonstrate altered BMP4 expression in vitro after using small interfering RNAs (siRNAs) to reduce SALL4 expression. We conclude that SALL4 hypomorphic variants may influence eye development.
authors.affiliation: a Department of Pediatrics , University of California, San Francisco , San Francisco , California , USA.|b Department of Biochemistry, Faculty of Biological Sciences , Quaid-i-Azam University , Islamabad , Pakistan.
authors.forename: E
authors.initials: E
authors.lastname: Ullah
authors.affiliation: a Department of Pediatrics , University of California, San Francisco , San Francisco , California , USA.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: c Department of Neurology , University of California, San Francisco , San Francisco , California , USA.
authors.forename: L
authors.initials: L
authors.lastname: Madireddy
authors.affiliation: d Cardiovascular Research Institute , University of California, San Francisco , San Francisco , California , USA.
authors.forename: R
authors.initials: R
authors.lastname: Lao
authors.affiliation: d Cardiovascular Research Institute , University of California, San Francisco , San Francisco , California , USA.
authors.forename: P
authors.initials: P
authors.lastname: Ling-Fung Tang
authors.affiliation: d Cardiovascular Research Institute , University of California, San Francisco , San Francisco , California , USA.
authors.forename: E
authors.initials: E
authors.lastname: Wan
authors.affiliation: e Division of Medical Genetics , Einstein Healthcare Network , Philadelphia , Pennsylvania , USA.
authors.forename: T
authors.initials: T
authors.lastname: Bardakjian
authors.affiliation: e Division of Medical Genetics , Einstein Healthcare Network , Philadelphia , Pennsylvania , USA.
authors.forename: S
authors.initials: S
authors.lastname: Kopinsky
authors.affiliation: d Cardiovascular Research Institute , University of California, San Francisco , San Francisco , California , USA.
authors.forename: P-Y
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: e Division of Medical Genetics , Einstein Healthcare Network , Philadelphia , Pennsylvania , USA.
authors.forename: A
authors.initials: A
authors.lastname: Schneider
authors.affiliation: c Department of Neurology , University of California, San Francisco , San Francisco , California , USA.
authors.forename: S
authors.initials: S
authors.lastname: Baranzini
authors.affiliation: b Department of Biochemistry, Faculty of Biological Sciences , Quaid-i-Azam University , Islamabad , Pakistan.
authors.forename: M
authors.initials: M
authors.lastname: Ansar
authors.affiliation: a Department of Pediatrics , University of California, San Francisco , San Francisco , California , USA.
authors.forename: A
authors.initials: A
authors.lastname: Slavotinek
mesh_terms: D003103:Coloboma / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006130:Growth Disorders / Q000235:genetics; D006343:Heart Septal Defects / Q000235:genetics; D006801:Humans; D007223:Infant; D008850:Microphthalmos / Q000235:genetics*; D020125:Mutation, Missense; D009901:Optic Nerve Diseases / Q000151:congenital* / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C472575:SALL4 protein, human; D014157:Transcription Factors
keywords: Anophthalmia; BMP4; SALL4; coloboma; microphthalmia