EMC10 – Intellectual Disability

This summary reviews the association between EMC10 and intellectual disability, a link that has been supported by evidence from multiple independent studies. Several families have been reported with a recessive inheritance pattern demonstrating that homozygous changes in EMC10 can result in a neurodevelopmental disorder characterized by global developmental delay, mild intellectual disability, and speech delay (PMID:32869858, PMID:35124540). The evidence encompasses case reports, multi-patient studies, and functional assessments that collectively point toward a causative effect of these variants.

Genetic studies reveal that affected individuals from distinct families harbor pathogenic variants in EMC10. In particular, a recurrent frameshift variant, c.287del (p.Gly96AlafsTer9), has been identified in at least two reports, indicating a founder effect in certain populations (PMID:35124540, PMID:33531666). Detailed segregation analyses in familial settings confirmed perfect co-segregation of the variant with the disease phenotype, strengthening the genetic evidence for EMC10 involvement.

The observed variant spectrum includes splice site and frameshift alterations, with the c.287del (p.Gly96AlafsTer9) variant being highlighted as a representative change. These genetic alterations disrupt the open reading frame and lead to premature truncation of the EMC10 protein. In addition to the clear recessive inheritance pattern, the recurrence of the frameshift variant across multiple families underscores its pathogenic relevance (PMID:33531666).

Functional studies provide important complementary evidence. For example, evaluation by RT‑qPCR in affected individuals shows a significant reduction in EMC10 gene expression, consistent with a loss‑of‑function mechanism (PMID:32869858). Animal and cellular model data (as documented in the multi‑patient studies) further support that reduced EMC10 levels impact key neurodevelopmental processes, aligning experimental findings with the clinical phenotype of intellectual disability and developmental delay.

Overall, the multi‑modal evidence—including approximately 20 probands across unrelated families, robust segregation data, and concordant functional studies—supports a strong ClinGen gene‑disease association for EMC10 and intellectual disability. Although additional studies continue to expand the phenotypic spectrum, the current collection of genetic and experimental data exceeds the ClinGen scoring maximum, confirming that defects in EMC10 play a critical role in neurodevelopment.

Key take‑home: Incorporating EMC10 genetic testing in diagnostic workflows can provide actionable insights and enable informed counseling for families affected by intellectual disability.

References

• Clinical genetics • 2020 • EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay PMID:32869858
• European journal of paediatric neurology • 2022 • The phenotype of homozygous EMC10 variant: A new syndrome with intellectual disability and language impairment PMID:35124540
• Genetics in medicine • 2021 • A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features PMID:33531666

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