Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

Breen, Michael S.; Fan, Xuanjia; Levy, Tess; Pollak, Rebecca M; Osman, Aya; Tocheva, Anna S.; Şahin, Mustafa; Berry‐Kravis, Elizabeth; Soorya, Latha; Thurm, Audrey; Powell, Craig M.; Bernstein, Jonathan A.; Kolevzon, Alexander; Buxbaum, Joseph D.

doi:10.1016/j.xhgg.2022.100145

Cited by 4 publications

(7 citation statements)

References 71 publications

(121 reference statements)

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“…54 Similarly, deletions that affect genes proximal to SHANK3 on 22q13.3, which almost always includes BRD1 (PIF = .96), have a substantial impact on transcriptomic profiles. 55 Mice heterozygous for Brd1 show cognitive defects. 56 Female mice heterozygous for Brd1 show negative affective symptoms that can be rescued with antidepressant medications.…”

Section: Resultsmentioning

confidence: 99%

“…A comparison of DNA methylation and metabolic profiles between PMS individuals with and without BRD1 deletion and healthy controls shows a striking divergence from normal methylation patterns and metabolic activities among those lacking one copy of BRD1 54 . Similarly, deletions that affect genes proximal to SHANK3 on 22q13.3, which almost always includes BRD1 (PIF = .96), have a substantial impact on transcriptomic profiles 55 . Mice heterozygous for Brd1 show cognitive defects 56 .…”

Section: Resultsmentioning

confidence: 99%

“…4,25,33,67 There may be loci along 22q13.3 especially important for certain phenotype characteristics, like lymphedema, 4,65 seizures 66,67,70,85 and metabolic profiles. 55 An apparent enigma has been assigning diversity (including severity) of phenotypes to deletion size in the face of diverse phenotypes among SHANK3 variants. 3,[12][13][14] The human phenotype diversity from different SHANK3 variants may be attributable to the complexity of the gene and evidence for multiple pathogenic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…The seven genes in Figure 3 have a moderate or high degree of contribution to fitness (LOEUF between 0.05 and 0.677) and additional evidence for contribution to the PMS phenotype. The overlapping influence of mechanisms on pathogenicity provides a possible explanation for both the deletion-size correlation with PMS severity 3,4,7,13,25,33,55,67 and the phenotypic similarity between SHANK3-unrelated and SHANK3-related cases. Although only seven genes have sufficient recent evidence for this review, a number of potentially important genes remain understudied.…”

Section: Discussionmentioning

confidence: 99%

“…The PMS phenotype is most notably correlated with neurodevelopmental impairments, including expressive language 4,25,33,67 . There may be loci along 22q13.3 especially important for certain phenotype characteristics, like lymphedema, 4,65 seizures 66,67,70,85 and metabolic profiles 55 . An apparent enigma has been assigning diversity (including severity) of phenotypes to deletion size in the face of diverse phenotypes among SHANK3 variants 3,12–14 .…”

Section: Discussionmentioning

confidence: 99%

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Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan‐McDermid syndrome

Mitz,

Boccuto,

Thurm

2024

Clinical Genetics

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Chromosome 22q13.3 deletion (Phelan‐McDermid) syndrome (PMS, OMIM 606232) is a rare genetic condition that impacts neurodevelopment. PMS most commonly results from heterozygous contiguous gene deletions that include the SHANK3 gene or likely pathogenic variants of SHANK3 (PMS‐SHANK3 related). Rarely, chromosomal rearrangements that spare SHANK3 share the same general phenotype (PMS‐SHANK3 unrelated). Very recent human and model system studies of genes that likely contribute to the PMS phenotype point to overlap in gene functions associated with neurodevelopment, synaptic formation, stress/inflammation and regulation of gene expression. In this review of recent findings, we describe the functional overlaps between SHANK3 and six partner genes of 22q13.3 (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, and TCF20), which suggest a model that explains the commonality between PMS‐SHANK3 related and PMS‐SHANK3 unrelated classes of PMS. These genes are likely not the only contributors to neurodevelopmental impairments in the region, but they are the best documented to date. The review provides evidence for the overlapping and likely synergistic contributions of these genes to the PMS phenotype.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan‐McDermid syndrome

Mitz,

Boccuto,

Thurm

2024

Clinical Genetics

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Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

Osman,

Mervosh,

Strat

et al. 2023

Brain, Behavior, and Immunity

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Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

Osman

Mervosh

Strat

et al. 2020

Preprint

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Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3 KO ), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3 KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3 KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3 KO mice. Additionally, we found that Shank3 KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.

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Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

Cited by 4 publications

References 71 publications

Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan‐McDermid syndrome

Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan‐McDermid syndrome

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

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