Developmental delay (DD) and intellectual disability (ID): Almost all individuals with ODLURO syndrome have global developmental delay. The majority are verbal, but present with speech delays with or without articulation issues. A few individuals showed speech regression. Four individuals with missense variants were not verbal. All reported individuals are able to walk independently, although many were delayed in achieving this milestone, and most presented with additional motor delays. The majority of affected individuals had intellectual disability, usually in the mild to moderate range with some in the low normal range.
Seizures: There is no consistent seizure semiology or epilepsy syndrome described in individuals with KMT2E-NDD. The presence of epilepsy may be related to genotype: all five individuals with missense variants had epilepsy, four of whom presented with treatment-resistant infantile-onset epilepsy. Among individuals with protein truncating variants, approximately 14% are reported to have seizures: phenotypes ranged from unprovoked seizures, febrile seizures, history of a single seizure, and treatment-resistant epilepsy. Sex-related differences have also been noted: in the initial description of this condition, epilepsy was present in 43% of females but in only 5% of males.
Autism: Autism is seen more frequently in males with KMT2E-NDD. No females have yet been reported to have autism.
Musculoskeletal features: Hypotonia is seen in about 46% of individuals with KMT2E-NDD. Joint laxity has also been reported.
Behavioral problems: Apart from autism, behavioral concerns appear to be relatively infrequent. The behavioral concerns reported include: stereotypies, skin-picking, self-injurious behavior, aggression, anxiety, and sensory integration disorder. At least two individuals have been diagnosed with attention-deficit/hyperactivity disorder (ADHD).
Growth: Growth parameters are variable for individuals, but most are in the normal range for height and weight, both at birth and later in life.
Gastrointestinal issues: Gastrointestinal symptoms have been reported in almost 50% of affected individuals and include reflux, vomiting, or reduced bowel motility.
Sleep disturbance: Sleep disturbances have been reported in approximately 47% of affected individuals and include frequent awakening and difficulties falling asleep.
Facial features: No characteristic pattern of dysmorphic features has been observed across individuals with KMT2E-NDD. Dysmorphic features are seen in a subset of individuals and commonly include macrocephaly, dolichocephaly, large forehead, deep-set eyes, periorbital fullness, prominent cheeks, and prominent nasolabial folds.
Neuroimaging: Approximately 20% of affected individuals showed nonspecific anomalies on brain imaging, which included abnormal corpus callosum, non-specific signal abnormalities in the white matter, decreased brain volume, ventriculomegaly, pachygyria, delayed myelination, small areas of heterotopia, or small localized cysts.
Inheritance: Most individuals with KMT2E have a de novo pathogenic variant. Affected individuals have a 50% chance of passing on this autosomal dominant condition. Parents of individuals with KMT2E-NDD who do not have the KMT2E pathogenic variant may have a low risk of having another child with this condition (2-3% risk) due to germline mosaicism.
KMT2E