SON is located in the chromosomal region 21q22.11, and consists of 12 exons, containing several functional domains indispensable for its function as a key modulator of RNA processing. These include an arginine/serine (RS)-rich domain, a G-patch domain and a double-stranded RNA-binding motif. Cellular staining of SON has proven its localization within the nuclear speckle, a subcellular intranuclear compartment enriched with pre-mRNA splicing factors.
Haploinsufficiency of SON is proven to be pathogenic and its inheritance pattern is autosomal dominant. Pathogenic variants in SON often occur ‘de novo’, referring the presence of the mutation in the affected individual, but absent in the DNA of the parents. All pathogenic variants so far have been reported to be a loss-of-function variant. Mainly truncating frameshift variants have been reported in affected individuals. Also nonsense variants, an in-frame deletion of eight amino acids, a substitution affecting the RS-region and a complete gene deletion have been described. To date, most pathogenic variants are located in exon 3, which is present in all isoforms of SON. The latter is likely explained by the fact that exon 3 accounts for 82% of the coding region of the SON gene.
Normally, SON facilitates spliceosome recruitment to the RNA Pol II complex and enhances splicing. Hence, the downstream effect of SON haploinsufficiency is characterized by erroneous splicing of transcripts under the control of SON. The result of SON haploinsufficiency is that there is too little correctly spliced mRNA of downstream SON targets. Importantly, as some of these downstream genes are known to cause disease by haploinsufficiency themselves, some of the clinical features observed in ZTTK syndrome can be explained by the dysregulation of these genes, rather than the haploinsufficiency of SON itself.
Whole-Exome Sequencing (followed by Sanger confirmation if needed) and analysis of parental samples are a good method to detect pathogenic variants in SON and to confirm their ‘de novo’ status.