A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Wu, Yuanyuan; Liu, Fang; Wan, Ruihua; Jiao, Baohua

doi:10.3389/fgene.2023.1153284

Cited by 3 publications

(1 citation statement)

References 33 publications

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“…Here, we report 18 new patients with heterozygous variants in SETD2 . So far, 33 patients have been reported with SETD2 variants [ 2 , 3 , 4 , 13 , 15 , 22 , 23 , 24 , 25 , 26 ]. Thus, this report reviewed and summarized the information of 51 patients and emphasized the clinical heterogeneity in individuals carrying these SETD2 variants.…”

Section: Discussionmentioning

confidence: 99%

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature

Parra,

Rabin,

Pappas

et al. 2023

Genes

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SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan–Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin–Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

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Section: Discussionmentioning

confidence: 99%

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature

Parra,

Rabin,

Pappas

et al. 2023

Genes

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SETD2 promotes PAF1C interactions with the elongating RNA Pol II and is required for neuronal differentiation

Ambrosi,

Pfaendler,

Butz

et al. 2024

Preprint

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Chromatin modifications are relevant for mammalian development and their aberrant deposition is associated with human disease. While the mechanisms that deposit and remove these modifications have been largely elucidated, their role in regulating gene activity during cellular differentiation have yet to be completely understood. By differentiating a panel of mouse embryonic stem cells lacking major chromatin regulators towards neuronal cells, we identified their requirement at different stages of cellular differentiation. We show that the H3K36me3 methyltransferase SETD2 is important for the establishment of neuronal gene expression during late stages of differentiation, but is dispensable once the cells have fully differentiated. This function is largely independent of the histone methyltransferase activity. By measuring the protein interaction network of elongating RNA Pol II, we identify a novel role for SETD2 in mediating interactions between the PAF1 complex and the elongating RNA Pol II, which is required to ensure optimal transcriptional processivity of neuronal genes.

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Cellular and molecular functions of SETD2 in the central nervous system

Mitchell,

Thor,

Piper

2023

Journal of Cell Science

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The covalent modification of histones is critical for many biological functions in mammals, including gene regulation and chromatin structure. Posttranslational histone modifications are added and removed by specialised ‘writer’ and ‘eraser’ enzymes, respectively. One such writer protein implicated in a wide range of cellular processes is SET domain-containing 2 (SETD2), a histone methyltransferase that catalyses the trimethylation of lysine 36 on histone H3 (H3K36me3). Recently, SETD2 has also been found to modify proteins other than histones, including actin and tubulin. The emerging roles of SETD2 in the development and function of the mammalian central nervous system (CNS) are of particular interest as several SETD2 variants have been implicated in neurodevelopmental disorders, such as autism spectrum disorder and the overgrowth disorder Luscan–Lumish syndrome. Here, we summarise the numerous roles of SETD2 in mammalian cellular functions and development, with a focus on the CNS. We also provide an overview of the consequences of SETD2 variants in human disease and discuss future directions for understanding essential cellular functions of SETD2.

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A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Cited by 3 publications

References 33 publications

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature

SETD2 promotes PAF1C interactions with the elongating RNA Pol II and is required for neuronal differentiation

Cellular and molecular functions of SETD2 in the central nervous system

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