A homozygous synonymous variant in SMG5, encoding a nonsense-mediated mRNA decay factor, causes developmental delay with growth retardation and relative macrocephaly.

The nonsense-mediated mRNA decay (NMD) pathway is a translation-dependent mechanism that maintains cellular RNA homeostasis by eliminating mRNAs containing a premature termination codon (PTC). NMD also targets ~ 15% of all physiological coding and non-coding spliced transcripts, thereby playing a significant role in shaping the cellular transcriptome. SMG5 is one of several NMD effector proteins required for the cleavage of mRNAs. In a female patient with craniofacial dysmorphism, developmental delay, severe growth retardation, and relative macrocephaly, we identified the homozygous synonymous variant c.2967G > A; p.Gln989 = in SMG5, affecting the last base of the penultimate exon. In patient fibroblasts, most of the SMG5 pre-mRNAs were aberrantly spliced, while a small proportion of canonically spliced SMG5 transcripts was found. Levels of SMG5 were reduced to ~ 25%. We identified a significant increase in the total protein amount and the size of the cell, Golgi apparatus, and nucleus in patient-derived fibroblasts. Cell proliferation was compromised, and the cell cycle was delayed. Patient fibroblasts showed global transcriptional dysregulation, with genes involved in nucleosome assembly and organization being upregulated and downregulated genes associated with differentiation, development, and morphogenesis. We found a global upregulation of NMD-sensitive transcripts, including a significant and experimentally validated increase in the relative abundance of naturally occurring PTC-containing transcripts of the splicing factor genes SRSF2, SRSF4, SRSF6, and SF3B3 in the patient’s fibroblasts. Together, our findings indicate that the homozygous synonymous SMG5 variant c.2967G > A acts as a hypomorphic allele, associated with mild inhibition of the NMD pathway and underlying the patient’s phenotype.