Case report and literature review of neurodevelopmental syndrome linked to DOT1L variants

The DOT1L gene encodes a histone lysine methyltransferase that has the distinctive characteristic of being composed of a DOT1 catalytic domain that targets lysine 79 of the core globular domain of histone H3. DOT1L missense variants have recently been implicated in an autosomal dominant inheritance syndrome with developmental delay and congenital anomalies in postnatal cohorts. We report the twenty-sixth patient with this disorder.

Trio genome sequencing (GS) was performed in a patient with developmental delay.

Clinical examination showed a predominant global developmental delay affecting language, with cerebral abnormalities visible on magnetic resonance imaging, hypotonia, and ophthalmological and musculoskeletal abnormalities. GS revealed a de novo heterozygous missense variant in exon 3 of DOT1L (c.161C > T; p.(Ala54Val)), which is reported for the first time as the cause of developmental delay and congenital anomalies.

Among the 26 reported patients, 23 have missense variants, two have truncating variants, and one has an in-frame deletion. The mode of transmission is predominantly de novo. Current studies indicate multiple pathogenic mechanisms underlying DOT1L-related disorder, including both gain-of-function and loss-of-function effects, underscoring the complexity of the disease etiology. Although the gene exhibits intolerance to loss-of-function variants, a considerable number of truncating variants are observed in control populations, suggesting incomplete penetrance and heterogeneity in the phenotypic expression of DOT1L-associated disorder. No phenotype-genotype correlation could be established. Among reported patients, including ours, the most consistent clinical manifestations are global developmental delay, predominantly affecting language and behavior, and possibly distinctive facial features.