This report describes Stolerman neurodevelopmental syndrome, a disorder caused by heterozygous, usually de novo, variants in the KDM6B gene. KDM6B encodes a demethylase that specifically demethylates lysine 27 of histone H3, and thus plays a key role in epigenetic processes controlling chromatin organization and gene silencing. There is a single orthologous gene in Drosophila, Utx, for which multiple genetic reagents have been generated, including classical loss-of-function alleles, RNAi-targeting constructs, alleles caused by insertional mutagenesis, overexpression constructs, and a CRISPR/Cas9-based TKO construct. Dmel\Utx is also orthologous to the human genes KDM6A and UTY.
Multiple UAS constructs of the human Hsap\KDM6B gene, including wild-type and human disease-implicated variants, have been introduced into flies. See the 'Disease-Implicated Variants' table below. Expression of the wild-type human gene results in distinctive phenotypes: lethality when using a ubiquitous driver and a wing-vein phenotype when using a wing-specific driver. Variants that failed to recapitulate these phenotypes were categorized as loss-of-function.
Animals homozygous for severe loss-of-function alleles of Utx typically die during the pupal stage. Using RNAi-effected knockdown of Utx in the mushroom body of the brain, memory and behavior phenotypes are observed.
[updated Mar. 2024 by FlyBase; FBrf0222196]
[STOLERMAN NEURODEVELOPMENTAL SYNDROME; NEDSST](https://omim.org/entry/618505)
[LYSINE DEMETHYLASE 6B; KDM6B](https://omim.org/entry/611577)
A developmental disorder characterized by mildly impaired global development apparent from infancy, poor speech acquisition, hypotonia with early feeding difficulties, mildly delayed walking, and variable behavioral abnormalities, such as autistic features, hyperactivity, or attention deficits. Individuals may have coarse facial features and mild distal skeletal abnormalities. [from MIM:618505; 2023.07.03]
Developmental delay (speech-language, motor, or global) was the most common feature of Stolerman neurodevelopmental syndrome in the observed cohort. Cognitive deficits were seen consistently in all individuals, but the overall phenotype was highly variable. Most individuals had mild intellectual disability (ID), autism spectrum disorder (ASD), or both. A significant proportion of the individuals showed various neurological abnormalities, including hypotonia (57%), sleep disturbances (32%), seizures (13%), and movement disorders (24%). Dysmorphic facial features were noted for most of the individuals, but coarse facial features were uncommon (Rots et al., 2023; pubmed:37196654; FBrf0256700)
Although most variants occur de novo, cases of inheritance from a mildly affected parent have occurred (Rots et al., 2023; pubmed:37196654; FBrf0256700).
KDM6B is categorized as a high confidence autism-related gene (score 1) in the SFARI gene database (https://gene.sfari.org/).
NEDSST is caused by heterozygous mutation in the KDM6B gene. Mutations occur de novo; the disorder occurs sporadically in patients with no family history of a similar disorder. [from MIM:618505; 2024.03.28]
KDM6B encodes a lysine-specific demethylase that specifically demethylates di- or tri-methylated lysine 27 of histone H3 (H3K27me2 or H3K27me3). H3K27 trimethylation is a repressive epigenetic mark controlling chromatin organization and gene silencing. The KDM6B protein can also demethylate non-histone proteins such as retinoblastoma protein.
Many to one: 3 human genes to 1 Drosophila gene.
High-scoring ortholog of human KDM6A, KDM6B, and UTY (1 Drosophila gene to 3 human).
