We previously reported a novel syndrome characterised by paediatric cataracts, dysmorphism, ectodermal features, and developmental delay with linkage to 1p35.3-p36.32 in a large Australian family. We hypothesised that a variant in the linkage region causes the syndrome. Whole genome and exome sequencing was used to identify rare (MAF<0.00022, gnomAD) and predicted deleterious (CADD PHRED score≥15) variants within the linkage region. Sanger sequencing was used to assess segregation in the wider family. Variants were prioritised based on conservation, location in regulatory motifs, constraint metrics, expression profile of the gene, and function of the proteins they encode.
Seventeen variants passed the filtering criteria and segregated with the disease. The three highest prioritised variants included two missense variants SELENON c.976G>A p.(Gly326Ser) and YTHDF2 c.910C>T p.(Pro304Ser), and one 5’ UTR variant HNRNPR c.-3259T>A. We investigated the impact of the gene on cataract formation in the lens of larval zebrafish using CRISPR-Cas9 knockouts of selenon, ythdf2, and hnrnpr in F0 zebrafish at 4 days post-fertilization. Knockout of hnrnpr resulted in significant cataract formation in experimental group (30.67%) compared to controls (12.5%) (p value= 0.006). Ongoing experiments using reporter gene assay aim to ascertain the effect at the variant level. HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, a member of the spliceosome C complex, functioning in pre-mRNA processing and transport. A study reported HNRNPR variants driving multisystem developmental defects and some phenotypes overlap with our family. However, HNRNPR has not been associated with cataract or cataract syndromes previously and will be a novel gene for paediatric cataract.