Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia

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....

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Bibliographic Details
Published in:Ophthalmic genetics 2017-07, Vol.38 (4), p.371-375
Main Authors: Ullah, E, Wu, D, Madireddy, L, Lao, R, Ling-Fung Tang, P, Wan, E, Bardakjian, T, Kopinsky, S, Kwok, P-Y, Schneider, A, Baranzini, S, Ansar, M, Slavotinek, A
Format: Article
Language:English
Subjects:
Coloboma - genetics
Exome - genetics
Female
Growth Disorders - genetics
Heart Septal Defects - genetics
Humans
Infant
Microphthalmos - genetics
Mutation, Missense
Optic Nerve Diseases - congenital
Optic Nerve Diseases - genetics
Pedigree
Phenotype
Polymerase Chain Reaction
Sequence Analysis, DNA
Transcription Factors - genetics
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Summary: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.
ISSN:1381-6810
1744-5094
DOI:10.1080/13816810.2016.1217550