Biallelic loss-of-function alleles of the SCLT1 gene cause a variable phenotypic spectrum of retinal ciliopathies

Abstract

Purpose : The SCLT1 protein is a core component of distal appendages (DAP), which anchors the cilium to the plasma membrane. Biallelic mutations have previously been reported in two cases with severe Oral-Facial-Digital (OFD) type IX syndrome, a severe ciliopathy, and non-syndromic inherited retinal disease (IRD) respectively. Here, we aimed to genetically, functionally and clinically characterize two families with non-syndromic IRD and a patient with syndromic IRD displaying developmental delay, obesity, and recurrent infections.

Methods : The three families included underwent ophthalmological examination including fundoscopy, full-field flash electroretinography (ERG), blue light autofluorescence imaging (BAF) imaging and optical coherence tomography (OCT). Genetic and functional analyses consisted of whole exome sequencing, SCLT1 expression analysis in patient fibroblasts, immunohistochemistry in human adult retina (HPA036561, Atlas Antibodies) and analysis of ciliary properties of induced primary cilia in patient fibroblasts.

Results : Compound heterozygous pathogenic SCLT1 variants were found in two families with non-syndromic IRD and in a patient with IRD, developmental delay, obesity, and recurrent infections. In the first two families a loss-of-function allele was found in trans to a hypomorphic allele, while in the index of the third family a loss-of-function allele was found in trans to a splice site variant causing an in-frame exon skip. These genotypes correlated with a rod-cone dystrophy phenotype, displaying a greyish retina with retinal vascular attenuation, but no intraretinal pigment migration.

SCLT1 expression analysis on patient fibroblasts showed a significantly reduced mRNA expression in comparison with controls. We demonstrated the localization of SCLT1 in human retinal tissue for the first time. Given the role of SCLT1 in the initiation of ciliogenesis as a core DAP protein, we investigated the properties of patient cilia by measuring induced primary cilia in patient and control fibroblasts, revealing significantly shorter primary cilia in patients compared to controls.

Conclusions : Our study adds to the wide range of ciliary phenotypes associated with biallelic loss-of-function SCLT1 variants, varying from non-syndromic IRD to OFD type IX at the end of the spectrum. We demonstrate that the severity correlates with the combination of mild, moderate and severe alleles.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.