A 5.3Mb deletion in chromosome 18q12.3 as the smallest region of overlap in two patients with expressive speech delay

Bouquillon, Sonia; Andrieux, Joris; Landais, Emilie; Duban‐Bedu, Bénédicte; Boidein, F.; Lenne, Bruno; Vallée, Louis; Leal, Teresinha; Doco‐Fenzy, Martine; Delobel, Bruno

doi:10.1016/j.ejmg.2010.11.009

Cited by 25 publications

(27 citation statements)

References 15 publications

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“…These patients also have moderate to severe intellectual disability, developmental and speech delay, and various behavioral abnormalities, including autism spectrum disorder, hyperactivity and aggressiveness. After reviewing the most recent clinical case reports of proximal del(18q) syndrome with precisely refined breakpoints, we noted in nine cases where deletions did not include CELF4 , only one patient suffered seizures (Cody et al 2007; Buysse et al 2008; Bouquillon et al 2011; Filges et al 2011; Marseglia et al 2012). Accordingly, the remaining six patients all had seizures and all had deletions that span CELF4 (Gribble et al 2005; Kotzot et al 2005; Cody et al 2007; Feenstra et al 2007; Bouquillon et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice

Sun

Wagnon

Mahaffey

et al. 2012

The Journal of Physiology

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Key points• Inappropriate electrochemical signalling between neurons is a central problem in epilepsy. Only a fraction of all heritable epilepsies are solved, and many are due to ion channel mutations.• Ion channels are cell surface molecules that initiate and coordinate electrochemical signalling, by allowing the right combination of ions to flow in and out of a neuron.• Ion channels may be regulated by other genes. We recently determined that the RNA-binding protein, 'CELF4' , affects expression of many molecules, including ion channels, to coordinate electrochemical signalling.• Here we conclude that a sodium channel called Na v 1.6 is the primary instigator of abnormal excitation when CELF4 is impaired.• Na v 1.6 expression is increased in the axon initial segment -a part of the neuron that initiates electrical activity -altering intrinsic excitability. We surmise that in a brain that already has difficulty regulating other molecules due to CELF4 deficiency, this leads to uncontrolled network excitation and seizures.Abstract Mice deficient for CELF4, a neuronal RNA-binding protein, have a complex seizure disorder that includes both convulsive and non-convulsive seizures, and is dependent upon Celf4 gene dosage and mouse strain background. It was previously shown that Celf4 is expressed predominantly in excitatory neurons, and that deficiency results in abnormal excitatory synaptic neurotransmission. To examine the physiological and molecular basis of this, we studied Celf4-deficient neurons in brain slices. Assessment of intrinsic properties of layer V cortical pyramidal neurons showed that neurons from mutant heterozygotes and homozygotes have a lower action potential (AP) initiation threshold and a larger AP gain when compared with wild-type neurons. Celf4 mutant neurons also demonstrate an increase in persistent sodium current (I NaP ) and a hyperpolarizing shift in the voltage dependence of activation. As part of a related study, we find that CELF4 directly binds Scn8a mRNA, encoding sodium channel Na v 1.6, the primary instigator of AP at the axon initial segment (AIS) and the main carrier of I NaP . In the present study we find that CELF4 deficiency results in a dramatic elevation in the expression of Na v 1.6 protein at the AIS in both null and heterozygous neurons. Together these results suggest that activation of Na v 1.6 plays a crucial role in seizure generation in this complex model of neurological disease.

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Section: Discussionmentioning

confidence: 99%

Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice

Sun

Wagnon

Mahaffey

et al. 2012

The Journal of Physiology

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“…27,28 Beyond FOXP2, little is known about genes related to speech, although recent studies have added CNTNAP2, CMIP, ATP2C2, RIT2, and SYT4 as potential genes of interest. 29,30 Future research into speech and language abilities in PMS would benefit from having detailed evaluations to better characterize the types of language delay specific to this syndrome.…”

Section: Speech and Language Delaymentioning

confidence: 99%

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan–McDermid syndrome

Sarasua

Dwivedi

Boccuto

et al. 2014

Genetics in Medicine

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“…SETBP1 is relatively large (388 337 bp), has 2 isoforms, and is expressed widely. Although little is known about its function, it is implicated in several neurodevelopmental conditions: SETBP1 haploinsufficiency is documented in expressive DLD [47][48][49] and intellectual disability. 50 Moreover, several tentative SNP associations were found between syntactic complexity and TNC that encodes tenascin, an extracellular matrix glycoprotein involved in neural development; TNC-deficient mice exhibit structural and functional cortical abnormalities, including atypical neuronal density and abnormal dendrite morphology.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population

et al. 2016

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BACKGROUND AND OBJECTIVE: Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder associated with negative outcomes in different domains; the etiology of DLD is unknown. To investigate the genetic underpinnings of DLD, we performed genome-wide association and whole exome sequencing studies in a geographically isolated population with a substantially elevated prevalence of the disorder (ie, the AZ sample).

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A 5.3Mb deletion in chromosome 18q12.3 as the smallest region of overlap in two patients with expressive speech delay

Cited by 25 publications

References 15 publications

Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice

Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan–McDermid syndrome

Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population

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