MEF2C deletions and mutations versus duplications: A clinical comparison

Novara, Francesca; Rizzo, Ambra; Bedini, Gloria; Girgenti, Vita; Susan, Esposito; Pantaleoni, Chiara; Ciccone, Roberto; Sciacca, Francesca L.; Achille, Valentina; Mina, Erika Della; Gana, Simone; Zuffardi, Orsetta; Estienne, Margherita

doi:10.1016/j.ejmg.2013.01.011

Cited by 24 publications

(28 citation statements)

References 21 publications

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“…The 30–50% loss of MEF2C due to the HAR mutation would likely affect tissues where the HAR is active and be similar to the heterozygous loss of MEF2C due to coding mutations. The phenotypic similarity between these patients and others with heterozygous MEF2C deletions—who often show severe ID, seizures, verbal and motor developmental delay, large ears, small chin, prominent forehead, and either hypo or hypertonia (Bienvenu et al, 2013; Novara et al, 2013) – suggests a possible role for this SNV in the individual’s phenotype.…”

Section: Methods Detailsmentioning

confidence: 71%

“…The family comprises healthy, first cousin parents with three healthy sons and two sons with ASD, ID, and mild dysmorphisms including small pointed chin and large ears, a phenotype commonly observed with MEF2C mutations (Bienvenu et al, 2013; Novara et al, 2013). The point mutation is present in low frequencies in the 1000G (0.7%), though more common in South Asia, and absent in healthy Middle Eastern controls.…”

Section: Methods Detailsmentioning

confidence: 99%

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Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

Doan

Bae

Cubelos

et al. 2016

Cell

283

343

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SUMMARY Comparative analyses have identified genomic regions potentially involved in human evolution, but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations–identified by whole genome and targeted “HAR-ome” sequencing–showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior.

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Section: Methods Detailsmentioning

confidence: 71%

Section: Methods Detailsmentioning

confidence: 99%

Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

Doan

Bae

Cubelos

et al. 2016

Cell

283

343

View full text Add to dashboard Cite

show abstract

“…For instance, a recent work confirmed the occurrence of jugular pits as a recurrent feature in those patients (Al-Shehhi et al, 2016). However, a milder phenotype with mild cognitive and speech disorders has been reported in patients with duplications (Novara et al, 2013). Epilepsy is not always present in patients with microdeletions.…”

Section: Discussionmentioning

confidence: 85%

MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review

Rocha

Sampaio²,

Rocha³

et al. 2016

European Journal of Medical Genetics

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“…MEF2C mutations, deletions or duplications have been linked with human epilepsy syndromes, developmental or intellectual disabilities, autism, and cerebral malformations (reviewed in (Novara et al 2013)). MEF2C deletions may also cause corpus callosum (47%) and other cerebral abnormalities (84%).…”

Section: Other Genetic Eieesmentioning

confidence: 99%

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

Galanopoulou

Moshé

2015

Neurobiology of Disease

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Early onset and infantile epileptic encephalopathies (EIEEs) are usually associated with medically intractable or difficult to treat epileptic seizures and prominent cognitive, neurodevelopmental and behavioral consequences. EIEEs have numerous etiologies that contribute to the inter- and intra-syndromic phenotypic variability. Etiologies include structural and metabolic or genetic etiologies although a significant percentage is of unknown cause. The need to better understand their pathogenic mechanisms and identify better therapies has driven the development of animal models of EIEEs. Several rodent models of infantile spasms have emerged that recapitulate various aspects of the disease. The acute models manifest epileptic spasms after induction and include the NMDA rat model, the NMDA model with prior prenatal betamethasone or perinatal stress exposure, and the γ-butyrolactone induced spasms in a mouse model of Down syndrome. The chronic models include the tetrodotoxin rat model, the aristaless related homeobox X-linked (Arx) mouse models and the multiple-hit rat model of infantile spasms. We will discuss the main features and findings from these models on target mechanisms and emerging therapies. Genetic models have also provided interesting data on the pathogenesis of Dravet syndrome and proposed new therapies for testing. The genetic associations of many of the EIEEs have also been tested in rodent models as to their pathogenicity. Finally, several models have tested the impact of subclinical epileptiform discharges on brain function. The impact of these advances in animal modeling for therapy development will be discussed.

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MEF2C deletions and mutations versus duplications: A clinical comparison

Cited by 24 publications

References 21 publications

Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

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