Two missense mutations in <i>SALL4</i> 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 <i>SALL4</i> - c.[575C&gt;A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G&gt;C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency for <i>SALL4</i> 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 <i>SALL4</i> 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. <i>SALL4</i> is expressed in the developing lens and regulates <i>BMP4</i>, leading us to speculate that altered <i>BMP4</i> expression was responsible for the eye defects, but we could not demonstrate altered <i>BMP4</i> expression <i>in vitro</i> after using small interfering RNAs (siRNAs) to reduce <i>SALL4</i> expression. We conclude that <i>SALL4</i> hypomorphic variants may influence eye development.