Submission Details

The SMG8 (suppressor with morphogenetic effects on genitalia 8) gene is located on chromosome 17 (17q22) and encodes a protein that serves as a nonsense mediated mRNA decay factor, binding SMG9 to facilitate the recruitment of SMG1 to the SURF complex (Yamashita et al., 2009, PMID:19417104). SMG8 was first reported in relation to autosomal recessive Alzahrani-Kuwahara syndrome (ALKUS) in 2020 (Alzahrani et. al., PMID:33242396). The ALKUS clinical presentation is characterized by early onset severe global developmental delay, intellectual disability, microcephaly, facial dysmorphism, variable congenital heart malformations, and variable eye malformations (OMIM: 613175). Genetic and clinical evidence reviewed in the curation of this gene-disease relationship included four Middle Eastern probands from consanguineous families with four unique homozygous variants. Each proband had at least one affected sibling with the same genotype and phenotype (Alzahrani et al., 2020, PMID:33242396, LOD score 3). A fifth affected Middle Eastern proband with a fifth homozygous variant was published separately (Abdel-Salam et al., 2021, PMID: 34761517), and a sixth proband from a non-consanguineous Brazilian family was found to have two additional previously unreported variants (1 nonsense, 1 frameshift) in trans based on parental testing (Fernandes et al., 2023, PMID: 37194129). The molecular mechanism of disease appears to be biallelic loss of function (5 out of 7 of the published variants are protein-truncating variants and the two missense variants are predicted to disrupt the binding of SMG8 to its partner SMG9). This gene-disease relationship is also supported by protein interactions, functional alterations, and rescue in a cell culture model. SMG9 variants cause a different syndrome (Shaheen et al., 2016, PMID: 27018474, MONDO:0014833) with a similar clinical presentation to that observed in ALKUS patients. SMG8 and SMG9 interact and the loss of the SMG8 C-terminus results in loss of SMG1 inhibition, independently disrupting nonsense-mediated decay (Zhu et al., 2019, PMID: 31729466). Depletion of SMG8 in Ullrich’s disease patient fibroblasts rescued an NMD-exacerbated mutant phenotype (Usuki et. al. 2013, PMID: 23983263). In summary, there is definitive genetic and experimental evidence supporting the relationship between SMG8 and autosomal recessive ALKUS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This definitive classification was approved by the ClinGen Syndromic Disorders GCEP in the meeting on November 1, 2023 (SOP Version 10).