De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes.

SRSF3

De novo SRSF3 variants (missense in the RNA recognition motif, C-terminal truncations) reducing binding to polyadenylated RNA, C-terminal phosphorylation and nucleocytoplasmic shuttling

This study reports nine individuals with de novo variants in SRSF3, which encodes an SR-family splicing factor, with variable developmental phenotypes dominated by developmental delay and/or mild to moderate intellectual disability. The variants include two missense changes at highly conserved residues of the RNA recognition motif (p.Asp61His, p.Ser81Trp), three frameshifts and a recurrent nonsense variant (p.Arg149Ter). For the c.330_331del variant, nonsense-mediated decay of variant transcripts was confirmed in fibroblasts by RT-PCR and RNA-seq, yet overall mRNA and protein levels were comparable to controls, suggesting compensation. In HEK293T cells, the variants reduced complex formation with polyadenylated RNA, and C-terminally truncated proteins were unstable, less phosphorylated and showed reduced nucleocytoplasmic shuttling.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A new neurodevelopmental disorder gene, encoding an essential splicing factor, whose mechanism is not simply haploinsufficiency: missense and C-terminal truncating variants have distinct functional defects, a proposed explanation for phenotypic variability. A useful point for exome and genome interpretation: a truncating variant predicted and confirmed to undergo NMD is not associated here with any overall drop in protein, so loss-of-function prediction alone is not enough. With nine patients, the clinical spectrum is still too narrow for prognostic counselling.

Analysis by Dr Thibaut Benquey