Novel truncating SF1 gene variant in a family with mild neurodevelopmental disorder: expanding the phenotype of SF1-related spliceosomopathy spectrum

Abstract

The SF1 gene encodes the splicing factor 1, a part of the splicing machinery. Recently, loss-of-function (LoF) variants in the SF1 gene have been suggested as a molecular cause of a neurodevelopmental spliceosomopathy. We report a unique familial case of a novel truncating variant in a single Czech family presenting with mild neurodevelopmental disorders (NDD) and variable congenital abnormalities. The c.1764_1776del variant in the last exon of the SF1 gene (NM_004630.4) was identified through exome sequencing in three affected family members. Functional analyses at the transcriptional level confirmed that this alteration does not trigger nonsense-mediated decay (NMD), and aberrant transcripts with premature termination codons are preserved. This study expands the spectrum of pathogenic variants involved in the development of new SF1 -related spliceosomopathy and its diverse phenotypic effects. Our data emphasise the clinical benefits of comprehensive exome sequencing for uncovering new gene-disease connections.