KMT2E – O'Donnell-Luria-Rodan Syndrome

This summary delineates the association between KMT2E (HGNC:18541) and O'Donnell-Luria-Rodan syndrome (MONDO_0032793), a neurodevelopmental disorder primarily characterized by global developmental delay, seizures, and other neurological manifestations. The syndrome is inherited in an autosomal dominant manner and has been reported in multiple independent case reports as well as in multi‐patient studies (PMID:35273928, PMID:39709003).

Robust genetic evidence supports the causative role of KMT2E in this disorder. Several studies have identified de novo variants, including splice, frameshift, and structural rearrangements, in unrelated individuals. For example, a de novo splicing variant (c.1248+1G>T) in a Chinese proband resulted in exon skipping and subsequent mRNA decay, while additional reports have detected both truncating and synonymous changes that impact splicing (PMID:35273928, PMID:37157895).

Among the reported variants, the synonymous alteration c.186G>A (p.Ala62=) exemplifies a compelling molecular finding. Although synonymous at first glance, in silico predictions and transcript analyses demonstrated that this variant leads to aberrant splicing events (PMID:38674365). Its inclusion in the mutational spectrum solidifies the gene’s role in disease pathogenesis.

Functional studies provide moderate additional support by validating the pathogenicity of identified variants. In vitro minigene splice assays and reverse transcription PCR experiments have confirmed that the aberrant splicing caused by these variants leads to loss of normal KMT2E mRNA transcripts, thereby reinforcing the deleterious mechanism implicated in O'Donnell-Luria-Rodan syndrome (PMID:35273928, PMID:40070083).

The phenotypic spectrum described in these studies is broad and includes global developmental delay (HP:0001263), seizures (HP:0001250), autism (HP:0000717), hypotonia (HP:0001252), macrocephaly (HP:0000256), as well as additional features such as feeding difficulties and sleep abnormalities. Together, these observations substantiate a multi-system impact of KMT2E disruption and underscore the utility of comprehensive genetic evaluation in affected patients (PMID:32691224, PMID:40048818).

In conclusion, the convergence of extensive genetic data and supportive functional studies establishes a strong association between KMT2E mutations and O'Donnell-Luria-Rodan syndrome. This integrated evidence not only enhances diagnostic accuracy but also informs personalized therapeutic strategies, marking a significant advancement in the molecular diagnosis of neurodevelopmental disorders.

References

• Frontiers in Pediatrics • 2022 • Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient PMID:35273928
• Clinical Genetics • 2023 • Genome sequencing identifies KMT2E-disrupting cryptic structural variant in a female with O'Donnell-Luria-Rodan syndrome PMID:37157895
• Genes • 2024 • Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of the Pathogenetic Role of A Synonymous Variant c.186G>A in KMT2E Gene PMID:38674365
• La Radiologia Medica • 2021 • ODLURO syndrome: personal experience and review of the literature PMID:32691224
• International Journal of Developmental Neuroscience • 2025 • A Novel KMT2E Splicing Variant as a Cause of O'Donnell-Luria-Rodan Syndrome With West Syndrome: Expansion of the Phenotype and Genotype PMID:40070083
• Epilepsy & Behavior • 2025 • Genotype-phenotype correlation of ODLURO syndrome comorbid epilepsy associated with KMT2E variations: Report on a novel case and systematic literature review PMID:40048818

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