Thus far, two pathogenic germline hemizygous frameshift variants in the last exon of the ZRSR2gene have been reported:
• NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23): this variant was identified by exome sequencing in two affected boys from one family
• NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24): this variant was detected by exome sequencing in 7 affected males from 5 unrelated families. This variant occurred de novo in one patient, and was maternally inherited in all other affected individuals.
The inheritance pattern is consistent with an X-linked recessive inheritance.
Transcriptome analysis in patient fibroblasts showed evidence of nonsense-mediated decay escape, presumably leading to a truncated protein with residual function. The reported pathogenic variants likely disrupt the C-terminal RS domain of ZRSR2, which was shown to mediate protein-protein interactions with other Serine/Arginine-rich proteins. Hemizygous loss-of-function variants in ZRSR2are presumed to be embryonically lethal in males. This is reflected by germline mutational constraint for hemizygous ZRSR2loss-of-function variants in the reference databases, such as GnomAD.
The gene ZRSR2encodes a splicing factor of the minor spliceosome. The minor spliceosome complex recognizes a subset of introns, called ‘minor’ introns, representing 0.35% of human introns. The abovementioned pathogenic variants in ZRSR2 are associated with abnormal splicing (intron retention) of these minor introns, causing splicing defects in downstream targets of ZRSR2. Among these targets are other genes that are known to be associated with other types of OFD syndrome.
ZRSR2