Syndromes Hidden within the 16p11.2 Deletion Region

Poot, Martin

doi:10.1159/000490845

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…MVP regulates the intracellular localization of the protein PTEN, which can antagonize PI3K/Akt. 82 , 83 This disruption, coupled with the lack of JNK and ERK response to BDNF shown here, suggests a broadly altered intracellular response to BDNF with the 16p11.2 DUP—potentially a key component of the neurodevelopmental pathology observed in 16p11.2 CNV syndromes. Indeed, BDNF is not only a critical growth factor during development.…”

Section: Discussionmentioning

confidence: 77%

BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome

Willis

Pratt

Morris

2020

Schizophrenia Bulletin

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Schizophrenia (SZ) is a neurodevelopmental disorder caused by the interaction of genetic and environmental risk factors. One of the strongest genetic risk variants is duplication (DUP) of chr.16p11.2. SZ is characterized by cortical gamma-amino-butyric acid (GABA)ergic interneuron dysfunction and disruption to surrounding extracellular matrix structures, perineuronal nets (PNNs). Developmental maturation of GABAergic interneurons, and also the resulting closure of the critical period of cortical plasticity, is regulated by brain-derived neurotrophic factor (BDNF), although the mechanisms involved are unknown. Here, we show that BDNF promotes GABAergic interneuron and PNN maturation through JNK signaling. In mice reproducing the 16p11.2 DUP, where the JNK upstream activator Taok2 is overexpressed, we find that JNK is overactive and there are developmental abnormalities in PNNs, which persist into adulthood. Prefrontal cortex parvalbumin (PVB) expression is reduced, while PNN intensity is increased. Additionally, we report a unique role for TAOK2 signaling in the regulation of PVB interneurons. Our work implicates TAOK2-JNK signaling in cortical interneuron and PNN development, and in the responses to BDNF. It also demonstrates that over-activation of this pathway in conditions associated with SZ risk causes long-lasting disruption in cortical interneurons.

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Section: Discussionmentioning

confidence: 77%

BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome

Willis

Pratt

Morris

2020

Schizophrenia Bulletin

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“…Furthermore, corroborating the obesity associations identified by PheWAS in the present analysis, the aggregate NDD CNVs were significantly associated with a quantitative outcome, increased BMI. While the 16p11.2 deletion is a well-characterized risk factor for obesity, this implicates the potential role of other NDD CNVs in obesity . The association between NDD CNVs and obesity, including BMI, may be explored further, as studies to date are limited one-off studies of obesity in specific CNV syndromes, with some clinical and molecular reports indicating a need for more systematic, in-depth investigation .…”

Section: Discussionmentioning

confidence: 99%

Clinical Characterization of Copy Number Variants Associated With Neurodevelopmental Disorders in a Large-scale Multiancestry Biobank

et al. 2022

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IMPORTANCE Past studies identified rare copy number variants (CNVs) as risk factors for neurodevelopmental disorders (NDDs), including autism spectrum disorder and schizophrenia. However, the clinical characterization of NDD CNVs is understudied in population cohorts unselected for neuropsychiatric disorders and in cohorts of diverse ancestry.OBJECTIVE To identify individuals harboring NDD CNVs in a multiancestry biobank and to query their enrichment for select neuropsychiatric disorders as well as association with multiple medical disorders. DESIGN, SETTINGS, AND PARTICIPANTSIn a series of phenotypic enrichment and association analyses, NDD CNVs were clinically characterized among 24 877 participants in the BioMe biobank, an electronic health record-linked biobank derived from the Mount Sinai Health System, New York, New York. Participants were recruited into the biobank since September 2007 across diverse ancestry and medical and neuropsychiatric specialties. For the current analyses, electronic health record data were analyzed from May 2004 through May 2019.MAIN OUTCOMES AND MEASURES NDD CNVs were identified using a consensus of 2 CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by novel in-silico clinical assessments. RESULTSOf 24 877 participants, 14 586 (58.7%) were female; self-reported ancestry categories included 5965 (24.0%) who were of African ancestry, 7892 (31.7%) who were of European ancestry, and 8536 (34.3%) who were of Hispanic ancestry; and the mean (SD) age was 50.5 (17.3) years. Among 24 877 individuals, the prevalence of 64 NDD CNVs was 2.5% (n = 627), with prevalence varying by locus, corroborating the presence of some relatively highly prevalent NDD CNVs (eg, 15q11.2 deletion/duplication). An aggregate set of NDD CNVs were enriched for congenital disorders (odds ratio, 2.0; 95% CI, 1.1-3.5; P = .01) and major depressive disorder (odds ratio, 1.5; 95% CI, 1.1-2.0; P = .01). In a meta-analysis of medical diagnoses (n = 195 hierarchically clustered diagnostic codes), NDD CNVs were significantly associated with several medical outcomes, including essential hypertension (z score = 3.6; P = 2.8 × 10 −4 ), kidney failure (z score = 3.3; P = 1.1 × 10 −3 ), and obstructive sleep apnea (z score = 3.4; P = 8.1 × 10 −4 ) and, in another analysis, morbid obesity (z score = 3.8; P = 1.3 × 10 −4 ). Further, NDD CNVs were associated with increased body mass index in a multiancestry analysis (β = 0.19; 95% CI, 0.10-0.31; P = .003). For 36 common serum tests, there was no association with NDD CNVs.CONCLUSIONS AND RELEVANCE Clinical features of individuals harboring NDD CNVs were elucidated in a large-scale, multiancestry biobank, identifying enrichments for congenital disorders and major depressive disorder as well as associations with several medical outcomes, including hypertension, kidney failure, and obesity and obesity-related phenotypes, specifically obstructive sleep apnea and increased body mass index. The association between NDD CNVs and obesity outcomes indi...

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“…CNVs, which are the most common form of structural variations in the human genome [ 177 ] and may take the form of duplications or deletions, have been identified to be one of the risk factors for developing ASD [ 178 ]. According to the contributing papers in this cluster, the most-researched gene loci is 16p11.2 [ 179 , 180 , 181 , 182 , 183 , 184 , 185 ], which codes for proteins involved in cortical development [ 186 ]. Of the cited documents, some of the most widely cited documents indeed focused on 16p11.2 microdeletion and microduplication [ 187 ] (citation frequency of 69) and others examined CNV similarities between ASD and schizophrenia (e.g., Marshall et al [ 188 ] with a citation frequency of 56 and Stefansson et al [ 189 ] with a citation frequency of 50).…”

Section: Discussionmentioning

confidence: 99%

Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022

Lim

Carollo

Dimitriou³

et al. 2022

Genes

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Genetic research in Autism Spectrum Disorder (ASD) has progressed tremendously in recent decades. Dozens of genetic loci and hundreds of alterations in the genetic sequence, expression, epigenetic transformation, and interactions with other physiological and environmental systems have been found to increase the likelihood of developing ASD. There is therefore a need to represent this wide-ranging yet voluminous body of literature in a systematic manner so that this information can be synthesised and understood at a macro level. Therefore, this study made use of scientometric methods, particularly document co-citation analysis (DCA), to systematically review literature on ASD genetic research from 2018 to 2022. A total of 14,818 articles were extracted from Scopus and analyzed with CiteSpace. An optimized DCA analysis revealed that recent literature on ASD genetic research can be broadly organised into 12 major clusters representing various sub-topics. These clusters are briefly described in the manuscript and potential applications of this study are discussed.

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Syndromes Hidden within the 16p11.2 Deletion Region

Cited by 5 publications

References 39 publications

BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome

BDNF and JNK Signaling Modulate Cortical Interneuron and Perineuronal Net Development: Implications for Schizophrenia-Linked 16p11.2 Duplication Syndrome

Clinical Characterization of Copy Number Variants Associated With Neurodevelopmental Disorders in a Large-scale Multiancestry Biobank

Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022

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