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.

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

“…They subsequently generated Sall2-null mice and, although no overt phenotypic abnormalities were observed, histological analysis of the eyes revealed a colobomatous phenotype, but with no evidence of microphthalmia. Of note, Ullah et al (Ullah et al 2017) recently identified by WES two missense variants in SALL4, another member of the spalt-like genes family, inherited in trans in a patient with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, cardiac defects and growth delay. Haploinsufficiency of SALL4 as a result of truncating mutations is linked to acro-reno-ocular syndrome (Okihiro syndrome, Duane-radial ray syndrome) (MIM#607323), the features of which include Duane syndrome, eye anomalies, as well as radial ray and renal anomalies (Kohlhase et al 2005).…”

Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia

“…Structural grading of foveal morphology was performed according to Thomas et al (30). The other family members exhibited normal OCT findings of the optic nerve and macular region ( (8,10,14,16,17,26,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46) and/or FVH (40,(47)(48)(49)(50)(51).…”

CUGC for syndromic microphthalmia including next-generation sequencing-based approaches

“…PITX3 variants associated with CTRCT11 are most commonly heterozygous and homozygous deletions and duplications [31,32]. Autosomal dominant heterozygous nonsense, frameshift, and missense SALL4 variants have been most frequently identified, while compound heterozygous and de novo variants are less common [33][34][35][36].…”