Abstract
Purpose :
Neurodevelopmental (ND) disorders account for >6% of global disease burden. Here, we present clinical characteristics and molecular genetic investigations of an autosomal dominant (AD) ND syndrome with coloboma associated with CSDE1 haploinsufficiency. We evaluated brain and retinal development in zebrafish csde1 mutant lines.
Methods :
Whole Exome Sequencing (WES) was performed to identify candidate disease genes. Zebrafish csde1 expression was assessed by in situ hybridization. To study the role of csde1 in eye and brain development, multiple indel zebrafish lines using CRISPR/Cas9 were generated. For Mendelian ratio assessment and survival curve, dead larvae were collected until 30dpf and genotyped. Homozygous fish were produced by in-crossing csde1+/- indel lines to produce embryos examined at 8 dpf for ocular abnormalities by immunohistochemistry and gross morphology.
Results :
Clinical presentation included iris coloboma, short stature, mild intellectual disability, and macrocephaly. WES revealed a heterozygous novel truncating variant (NM_001242891: c.248_249insA; p.Tyr83Ter) in CSDE1, a highly constrained gene encoding an RNA binding protein, segregating with phenotype. In zebrafish, expression of csde1 is dynamic across developmental stages, with prominent expression in eye and brain as early as 24 hpf. To understand the role of CSDE1 in eye and brain development, we generated CRISPR-induced frameshift alleles in zebrafish. Zebrafish csde1 nulls with exon 4 frameshift mutations exhibited gross developmental abnormalities including short body length (p<0.05) when compared with age-matched controls (csde1 +/+ and csde1+/-). Morphometric analysis of outer retina revealed significantly thinner ganglion cell layer & inner plexiform layer thickness. Currently, we are investigating retinal cell fate specification, ocular growth, and visual function in csde1 mutants.
Conclusions :
Our study identified a novel heterozygous truncating allele in CSDE1 associated with an AD neurodevelopmental syndrome with coloboma. Our findings strongly suggest that CSDE1 is critical for retinal development in humans and zebrafish.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.