A familial case of KMT5B-associated autosomal dominant neurodevelopmental disorder

We report a 6-year-old boy with global developmental delay, mild dysmorphic features, hypermetropia with astigmatism and exotropia, and cutaneous syndactyly of toes IV–V. An X-ray of the right foot revealed postaxial polysyndactyly (toes V–VI). Sleep EEG showed generalized epileptiform discharges. Growth parameters were within the normal range (65th percentile). The patient had previously undergone surgery for inguinal hernia and phimosis.
Family history was notable for similar facial features in the proband’s mother and maternal grandmother. The mother had macrocephaly (>97th percentile), epilepsy since early childhood, and mild ID. Brain MRI revealed right hippocampal sclerosis and focal cortical dysplasia of the medial parietal lobe. Despite right frontomedial parietal lobectomy and amygdalo-hippocampectomy, seizures persisted.
Exome sequencing identified a heterozygous nonsense variant in KMT5B (NM_017635.5:c.1708G>T, p.(Glu570*)). The same variant was present in the proband’s mother. Pathogenic variants in KMT5B, encoding a lysine methyltransferase involved in chromatin regulation, have been associated with autosomal dominant neurodevelopmental disorders. The functional impact of the stop mutation is currently under investigation, results of KMT5B episignatures and KMT5B expression is pending.