SMG8 and Alzahrani-Kuwahara Syndrome

The association between SMG8 and Alzahrani-Kuwahara syndrome is supported by multiple lines of evidence from independent case reports, multi‐patient studies, and functional assessments. In the initial report, a 27‐year‐old male with features of global developmental delay, facial dysmorphism, microcephaly, and pyramidal signs was identified to harbor compound heterozygous variants in SMG8, including the variant c.1159C>T (p.Arg387Ter) (PMID:37194129). This report was complemented by a multi‐patient study describing eight subjects from four different families and one additional unrelated family with either homozygous or compound heterozygous deleterious variants in SMG8, all demonstrating overlapping neurodevelopmental phenotypes with abnormal facial features and microcephaly (PMID:34761517).

Extensive genetic evidence supports an autosomal recessive mode of inheritance, with biallelic variants including nonsense and frameshift changes identified consistently across unrelated probands. The segregation data, while primarily limited to proband-centric reports, underscore the relevance of family-based analyses where compound heterozygosity or homozygosity for SMG8 variants correlates with the disease phenotype (PMID:37194129) and (PMID:34761517).

The variant spectrum in SMG8 includes changes such as c.1159C>T (p.Arg387Ter) that directly disrupt the protein product, consistent with a loss-of-function mechanism. The disruption of SMG8 function interferes with its role in regulating nonsense-mediated mRNA decay, which is crucial for neuronal development, thereby providing a genetic explanation for the observed clinical manifestations (PMID:34761517).

Functional studies further substantiate the disease mechanism. In particular, research demonstrated that SMG8 deficiency leads to increased phosphorylation of UPF1 and dysregulated mRNA expression, thereby confirming impaired inhibition of SMG1 kinase activity which is central to the NMD pathway (PMID:33242396). These experimental findings reinforce the pathogenicity of SMG8 variants and their role in the neurodevelopmental phenotype of Alzahrani-Kuwahara syndrome.

In summary, both genetic and functional data converge on a strong association between SMG8 variants and Alzahrani-Kuwahara syndrome. The evidence encompasses at least 9 probands from 5 unrelated families (PMID:34761517) with robust variant and segregation data, alongside mechanistic experiments that support a loss-of-function pathogenic mechanism. Although additional supporting evidence exists that exceeds the standard scoring maximum, the current body of literature is sufficient to inform diagnostic decision-making, support commercial use, and underpin future publications.

Key Take‑home sentence: The compelling genetic and functional evidence establishes SMG8 as a critical gene in Alzahrani-Kuwahara syndrome, ensuring its utility in diagnostic and therapeutic strategies.

References

• American journal of medical genetics. Part A • 2023 • Expanding the genetic spectrum of ALKU syndrome: Compound heterozygosity for two deleterious variants in SMG8 gene PMID:37194129
• American journal of medical genetics. Part A • 2022 • Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9-associated disease trait PMID:34761517
• American journal of human genetics • 2020 • Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans PMID:33242396

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