Inherited retinal diseases (IRDs) are a group of monogenic conditions that can lead
to progressive blindness. Their missing heritability is still considerable, due in
part to the presence of disease genes that await molecular identification. The purpose
of this work was to identify novel genetic associations with IRDs.Patients underwent
a comprehensive ophthalmological evaluation using standard-of-care tests, such as
detailed retinal imaging (macular OCT, short-wavelength fundus autofluorescence) and
electrophysiological testing. Exome and genome sequencing, as well as computer-assisted
data analysis were used for genotyping and detection of DNA variants. A minigene-driven
splicing assay was performed to validate the deleterious effects of one of such variants.We
identified 8 unrelated families from Hungary, the United States, Israel, and the Netherlands
with members presenting with a form of autosomal recessive and nonsyndromic retinal
degeneration, predominantly described as rod-cone dystrophy but also including cases
of cone / cone-rod dystrophy. Age of disease onset was very variable, with some patients
experiencing first symptoms during their fourth decade of life or later. Myopia greater
than 5 diopters was present in 5 of 7 cases with available refractive data, and retinal
detachment was reported in 2 cases. All ascertained patients carried biallelic loss-of-function
variants in UBAP1L (HGNC: 40028), a gene with unknown function and with homologies
to UBAP1, encoding a protein involved in ubiquitin metabolism. One of these pathogenic
variants, the intronic NM_001163692.2:c.910-7G>A substitution, was identified in five
unrelated families. Minigene-driven splicing assays in HEK293T cells confirmed that
this DNA change is responsible for the creation of a new acceptor splice site, resulting
in aberrant splicing.We identified UBAP1L as a novel IRD gene. Although its function
is currently unknown, UBAP1L is almost exclusively expressed in photoreceptors and
the retinal pigment epithelium, hence possibly explaining the link between pathogenic
variants in this gene and an ocular phenotype.
