ClinVar

In 5 patients from 3 unrelated Finnish families with neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies (NEDITPO; 619995), Rahikkala et al. (2022) identified a homozygous c.551T-C transition (c.551T-C, NM_019108.4) in the SMG9 gene, resulting in a val184-to-ala (V184A) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. RNA sequencing showed that the variant did not affect splicing or the expression level of SMG9 gene products, and allele-specific expression analysis did not find evidence of nonsense-mediated mRNA decay. Differential gene expression analysis identified an overall pattern of increased gene expression in several genes among affected patients. The authors speculated that SMG9 may have an inhibitory effect on gene expression, with this variant causing transcriptional upregulation. The variant was rare in the gnomAD database with an overall minor allele frequency of 0.0001627. The allele frequency was 34 times higher in the Finnish population than in non-Finnish Europeans. Haplotype analysis in the 3 Finnish families showed that the variant lies on a shared ancestral haplotype, suggesting that this is a Finnish founder variant. The authors noted the milder phenotype in patients with this homozygous missense variant compared to patients with homozygous loss-of-function variants in SMG9 who present with heart and brain malformation syndrome (616920).