16p11.2 Copy Number Variations and Neurodevelopmental Disorders

Rein, Benjamin; Yan, Zhen

doi:10.1016/j.tins.2020.09.001

Cited by 99 publications

(102 citation statements)

References 105 publications

(239 reference statements)

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“…TAOK2 is one of the 30 genes that are located in the 16p11.2 region. Recently, more psychiatric features like speech/language impairments, intellectual disability, motor/developmental delay, microcephaly and macrocephaly have been identified in patients with 16p11.2 microdeletion and microduplication (Steinman et al, 2016 ; Rein and Yan, 2020 ). Although it has been long been proposed that disruption of monogenic TAOK2 function might result in NDDs, the clear clinical evidence has only been presented recently.…”

Section: Clinical Association Between Tao Kinases and Nddsmentioning

confidence: 99%

“…Although TAOK2 contribution to 16p11.2 CNVs pathophysiology is quite convincing, it should be noted that it is TAOK2 and other genes (e.g., MAPK3 , SEZ6L2 and KCTD13 ) that act collectively to develop much complex and diverse 16p11.2 CNVs phenotypes (Krishnan et al, 2016 ), compared to individual gene mutations (Richter et al, 2018 ; Rein and Yan, 2020 ). In this review, we focus on TAOK2 function only since 16p11.2 CNVs related NDDs have recently been reviewed (Rein and Yan, 2020 ) and is also out of scope of the current study.…”

Section: Clinical Association Between Tao Kinases and Nddsmentioning

confidence: 99%

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Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

Pan

Yang

et al. 2021

Front. Mol. Neurosci.

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Despite the complexity of neurodevelopmental disorders (NDDs), from their genotype to phenotype, in the last few decades substantial progress has been made in understanding their pathophysiology. Recent accumulating evidence shows the relevance of genetic variants in thousand and one (TAO) kinases as major contributors to several NDDs. Although it is well-known that TAO kinases are a highly conserved family of STE20 kinase and play important roles in multiple biological processes, the emerging roles of TAO kinases in neurodevelopment and NDDs have yet to be intensively discussed. In this review article, we summarize the potential roles of the TAO kinases based on structural and biochemical analyses, present the genetic data from clinical investigations, and assess the mechanistic link between the mutations of TAO kinases, neuropathology, and behavioral impairment in NDDs. We then offer potential perspectives from basic research to clinical therapies, which may contribute to fully understanding how TAO kinases are involved in NDDs.

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Section: Clinical Association Between Tao Kinases and Nddsmentioning

confidence: 99%

Section: Clinical Association Between Tao Kinases and Nddsmentioning

confidence: 99%

Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

Pan

Yang

et al. 2021

Front. Mol. Neurosci.

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“…Among the hotspot regions particularly prone to genomic rearrangement is the chromosome numbered 16p11.2: this region, first described in 2009, is sized ~600 kb and contains 27–29 genes ( 26 ). A recent review ( 30 ) summarizes the clinical aspects of both deletion and duplications occurring in the 16p11.2 region. The presence of psychotic symptoms in patients with 16p11 duplication is ascertained by many authors ( 4 , 26 , 27 , 31 ), with a risk of SCZ increased from 8 to 25 times, depending on the studies.…”

Section: Introductionmentioning

confidence: 99%

“…Concerning inheritance pattern, both alterations follow an autosomal dominant model with reduced penetrance; most deletions occur de novo (60–76%) while most of the duplications are transmitted from an even mildly affected parent ( 30 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: The Association Between Chromosomal Anomalies and Cluster A Personality Disorders: The Case of Two Siblings With 16p11.2 Deletion and a Review of the Literature

et al. 2021

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Although several studies have shown the correlation between chromosomal rearrangements and the risk of developing psychotic disorders, such as schizophrenia, little attention has been given to identifying the genetic basis of pre-disposing personality so far. In this regard, a limited but significant number of studies seem to indicate an association between chromosomal anomalies and cluster A personality disorders (CAPD). Starting from the clinical description of two brothers affected by familial 16p11 deletion syndrome (OMIM #611913), both sharing cluster A and C personality traits, the aim of the present study is to critically review the literature regarding the correlation between chromosomal rearrangements and CAPD. A bibliographic search on PubMed has been conducted, and eight studies were finally included in our review. Most of the studies highlight the presence of schizotypal personality disorder in the 22q11.2 deletion syndrome, whose evolutionary course toward psychotic pictures is well-known. One study also identified a paranoid personality disorder in a patient with a deletion on chromosome 7q21.3. No studies have so far identified the presence of paranoid personality disorder in 16p11 deletion, as in the case of the two siblings we report, while its association with psychosis and autism is already known. Although further epidemiologic studies on broader populations are indicated, our observations might pave the way for the definition of new diagnostic subgroups of CAPD and psychotic disorders, in order to implement the clinical management of such complex conditions.

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“…In particular, heterozygous deletion mice – hereafter referred to as 16p11.2 del/+ mice – in each of these lines share basic phenotypes such as low body weight and perinatal mortality, and, importantly, also show behavioral phenotypes related to the symptoms of human 16p11.2 microdeletion carriers. These phenotypes include increased locomotor activity, stereotyped and repetitive behaviors, sleep deficits, recognition memory deficits, reward learning deficits, and social deficits (Angelakos et al, 2017; Arbogast et al, 2016; Grissom et al, 2017; Horev et al, 2011; Portmann et al, 2014; Rein & Yan, 2020; Walsh et al, 2018; Yang, Lewis, et al, 2015; Yang, Mahrt, et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Sex-specific stress-related behavioral phenotypes and central amygdala dysfunction in a mouse model of 16p11.2 microdeletion

Giovanniello

Ahrens

et al. 2020

Preprint

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Substantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders including autism spectrum disorders (ASD). Carriers of this deletion show divergent symptoms besides the core features of ASD, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. Here we report mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., the ‘16p11.2 del/+ mice’) have sex-specific anxiety-related behavioral and neural circuit changes. We found that female, but not male 16p11.2 del/+ mice showed enhanced fear generalization – a hallmark of anxiety disorders – after auditory fear conditioning, and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male 16p11.2 del/+ mice. Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome, and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.

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16p11.2 Copy Number Variations and Neurodevelopmental Disorders

Cited by 99 publications

References 105 publications

Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

Case Report: The Association Between Chromosomal Anomalies and Cluster A Personality Disorders: The Case of Two Siblings With 16p11.2 Deletion and a Review of the Literature

Sex-specific stress-related behavioral phenotypes and central amygdala dysfunction in a mouse model of 16p11.2 microdeletion

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