Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene

Fernandez, Thomas V.; Williams, Zsanett P.; Kline, Tina; Rajendran, Shreenath; Augustine, Farhan; Wright, Nicole; Sullivan, Catherine A. W.; Olfson, Emily; Abdallah, Sarah B.; Liu, Wenzhong; Hoffman, Ellen J.; Gupta, Abha R.; Singer, Harvey S.

doi:10.1371/journal.pone.0291978

Cited by 3 publications

(1 citation statement)

References 74 publications

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“…The aberrant size of the striatum is in line with the reduced performance of Kdm5b Δ/Δ mice in the accelerating rotarod task ( 47 ). De novo, likely gene disrupting variants in KDM5B have also been linked to primary motor stereotypies, another phenotype associated with alterations in the cerebellum ( 48 ) and cortico-striatal-thalamo-cortical pathways ( 49 ), ( 50-52 ). Abnormalities in these brain regions and pathways could underlie the repetitive behaviours observed in Kdm5b Δ/Δ mice.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Pérez-Sisqués,

Bhatt,

Caruso

et al. 2024

Preprint

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Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for regulating the trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the specific role of H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developingKdm5bmutant neocortex. These included elevated expression ofGrin2d. TheGrin2dgene product NMDAR2D was increased in synaptosomes isolated from theKdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associatedGrin2dgene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.

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Section: Discussionmentioning

confidence: 99%

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Pérez-Sisqués,

Bhatt,

Caruso

et al. 2024

Preprint

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Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes

Olfson,

Farhat,

Liu

et al. 2024

Nat Commun

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Research demonstrates the important role of genetic factors in attention-deficit/hyperactivity disorder (ADHD). DNA sequencing of families provides a powerful approach for identifying de novo (spontaneous) variants, leading to the discovery of hundreds of clinically informative risk genes for other childhood neurodevelopmental disorders. This approach has yet to be extensively leveraged in ADHD. We conduct whole-exome DNA sequencing in 152 families, comprising a child with ADHD and both biological parents, and demonstrate a significant enrichment of rare and ultra-rare de novo gene-damaging mutations in ADHD cases compared to unaffected controls. Combining these results with a large independent case-control DNA sequencing cohort (3206 ADHD cases and 5002 controls), we identify lysine demethylase 5B (KDM5B) as a high-confidence risk gene for ADHD and estimate that 1057 genes contribute to ADHD risk. Using our list of genes harboring ultra-rare de novo damaging variants, we show that these genes overlap with previously reported risk genes for other neuropsychiatric conditions and are enriched in several canonical biological pathways, suggesting early neurodevelopmental underpinnings of ADHD. This work provides insight into the biology of ADHD and demonstrates the discovery potential of DNA sequencing in larger parent-child trio cohorts.

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A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants

Borroto,

Michaud,

Hudon

et al. 2024

Genes

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Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

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Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene

Cited by 3 publications

References 74 publications

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes

A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants

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