EEF1B2 – Intellectual Disability

Recent evidence supports a strong association between biallelic loss‐of‑function variants in EEF1B2 and autosomal recessive intellectual disability. Multiple independent family studies have identified pathogenic variants in EEF1B2 that segregate with a consistent neurodevelopmental phenotype characterized by moderate intellectual disability and seizures (PMID:31845318).

In one study, a family with three affected siblings harbored a homozygous LoF variant, while a second family exhibited two affected siblings carrying a novel homozygous loss‐of‑function allele. In a separate multi‐patient study, compound heterozygous variants were identified in two additional patients. Such findings, representing approximately seven probands across three unrelated families (PMID:31845318, PMID:35015920), provide robust genetic evidence for the gene–disease link.

Genetic evidence is further exemplified by the recurrent identification of a loss‑of‑function variant; for instance, one reported variant is standardized as c.383C>A (p.Ser128Ter). This variant has been observed in families with autosomal recessive inheritance, and segregation studies within affected families have confirmed its pathogenic role. Such variant-specific data, coupled with consistent inheritance patterns, underpin the reliability of this association (PMID:31845318).

Functional analyses lend additional support to the role of EEF1B2 in neurodevelopment. Expression studies demonstrated significantly reduced mRNA and protein levels in affected individuals, while a zebrafish knockout model recapitulated key aspects of the human phenotype, including developmental abnormalities and seizure-like hyperactivity (PMID:35015920). These experimental studies underscore haploinsufficiency as the likely pathogenic mechanism.

Overall, the convergence of genetic, segregation, and functional data provides a coherent narrative that strongly supports the involvement of EEF1B2 in autosomal recessive intellectual disability. No conflicting evidence has been documented, and the collective data exceed the typical ClinGen scoring maximum, further validating the clinical utility of this association.

Key Take‑home Message: EEF1B2 genetic testing significantly aids the diagnostic evaluation of patients with autosomal recessive intellectual disability, enabling targeted management and counseling.

References

• Clinical Genetics • 2020 • New evidence that biallelic loss of function in EEF1B2 gene leads to intellectual disability PMID:31845318
• Human Mutation • 2022 • Novel biallelic loss of EEF1B2 function links to autosomal recessive intellectual disability PMID:35015920

Evidence Based Scoring (AI generated)