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ELMO2 – Ramon syndrome

In two independent case reports (PMID:29095483, PMID:38517102) a recessive association between ELMO2 and Ramon syndrome has been described. The first study detailed a consanguineous Lebanese family in which a patient presented with intellectual disability, seizures, and dental crowding, and where segregation analysis revealed an affected sibling (1 additional affected relative) (PMID:29095483). The reported variant, c.1817T>C (p.Ile606Ser), represents a novel homozygous missense change, while a second report identified a distinct predicted loss-of-function variant in a patient with gingival hypertrophy and neurodevelopmental delay (PMID:38517102). These genetic findings are complemented by the clinical features mapping to Ramon syndrome, including intellectual disability (HP:0001249), seizures (HP:0001250), dental crowding (HP:0000678), and neurodevelopmental delay (HP:0012758).

Preliminary functional assessments suggest that loss of ELMO2 function may disrupt critical cellular pathways, although detailed experimental studies remain limited. Overall, while the genetic evidence from two independent families with segregation supports a moderate level of genetic evidence, the small number of probands has resulted in a Limited overall gene-disease association classification. Key take‑home sentence: Despite the need for further validation, the identification of biallelic ELMO2 variants provides a promising diagnostic marker for Ramon syndrome.

References

  • Clinical genetics • 2018 • Homozygous mutation in ELMO2 may cause Ramon syndrome PMID:29095483
  • American journal of medical genetics. Part A • 2024 • ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review PMID:38517102

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Two independent families (2 probands) with segregation in additional affected relatives (total of 2) support a recessive association between ELMO2 and Ramon syndrome, although the limited number of cases restricts broader genotype-phenotype correlation (PMID:29095483, PMID:38517102).

Genetic Evidence

Moderate

The identification of a homozygous c.1817T>C (p.Ile606Ser) missense variant and a predicted loss-of-function allele across independent studies supports a moderate level of genetic evidence consistent with an autosomal recessive mode of inheritance.

Functional Evidence

Limited

Preliminary functional studies suggest that ELMO2 deficiency may lead to disruption of cellular pathways relevant to Ramon syndrome, but further experimental validation is required.