ELMOD3 & Autism Spectrum Disorder

The association between ELMOD3 and autism spectrum disorder (ASD) is based on limited but emerging genetic evidence. Several studies have identified copy number variants (CNVs) and gene fusion events involving ELMOD3 in patients with ASD, intellectual disability, and hearing impairment (PMID:30284680, PMID:31800155). Although ELMOD3 is well‑established in its role in nonsyndromic hearing loss through functional assays, the evidence for its contribution to ASD originates primarily from rare cases identified via CNV analyses in consanguineous families.

Genetic evidence for the ASD association derives from a report of a homozygous 2p11.2 deletion affecting multiple genes including ELMOD3, and a study identifying an ELMOD3‑SH2D6 gene fusion in four unrelated families with ASD. In these cases, the inheritance pattern appears to follow an autosomal recessive mode, which is consistent with the high inbreeding observed in affected populations. However, the overall count of unrelated probands with isolated ELMOD3 changes remains limited (PMID:30284680, PMID:31800155).

There is modest segregation data, with the reported CNVs and gene fusion being the primary findings supporting the gene‑disease link. No extensive segregation of point variants or multiple affected relatives carrying segregating alleles has yet been documented. The variant spectrum in the ASD context is derived mainly from large deletions and fusion events rather than single nucleotide changes. Nonetheless, these findings suggest that a disruption in ELMOD3 may contribute to neurodevelopmental deficits observed in affected individuals.

For the purpose of genetic reporting, one relevant coding variant identified in functional studies for ELMOD3 is c.512A>G (p.His171Arg). Although this missense variant has been characterized in the context of autosomal dominant nonsyndromic hearing loss, it is the only available HGVS‐compliant coding change for ELMOD3 and serves as a reference point for gene‐level variant reporting.

Functional studies have primarily focused on the role of ELMOD3 in hearing loss, demonstrating that mutations, such as p.His171Arg, alter protein stability and localization. These experiments support the hypothesis that ELMOD3 is involved in actin cytoskeletal regulation and sensory epithelial function. However, direct experimental functional evidence linking ELMOD3 to ASD-specific neurodevelopmental mechanisms is absent. This gap emphasizes the need for further mechanistic studies to clarify the role of ELMOD3 in ASD etiology.

In summary, while current genetic findings lend preliminary support to the potential involvement of ELMOD3 in autism spectrum disorder, the overall evidence is limited. The gene‑disease association may be secondary to the broader impact of contiguous gene deletions and complex rearrangements that span multiple genes. Clinicians should consider the possibility of ELMOD3 involvement in ASD, especially in contexts of consanguinity and combined neurodevelopmental phenotypes, but additional replication and functional studies are required to fully establish its clinical utility.

Key Take‑home: Although ELMOD3 is well‑characterized in hearing loss pathology, its association with autism spectrum disorder remains provisional; cautious interpretation in diagnostic decision‑making is warranted pending further genetic and experimental validation.

References

• Journal of applied genetics • 2019 • Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology PMID:30284680
• Journal of cellular and molecular medicine • 2020 • ELMOD3‑SH2D6 gene fusion as a possible co‑star actor in autism spectrum disorder scenario PMID:31800155

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