5q14.3 neurocutaneous syndrome: A novel continguous gene syndrome caused by simultaneous deletion of <i>RASA1</i> and <i>MEF2C</i>

Carr, C. W.; Zimmerman, Holly H.; Martin, Christa Lese; Vikkula, Miikka; Byrd, Adam; Abdul‐Rahman, Omar

doi:10.1002/ajmg.a.34059

Cited by 29 publications

(23 citation statements)

References 19 publications

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“…2a–g). The deletions in three subjects included RASA1 , implicated in the “5q14.3 neurocutaneous syndrome” [2], but only one subject in our cohort (LR12-031) had characteristic capillary malformation of the skin (Fig. 2h).…”

Section: Resultsmentioning

confidence: 99%

MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

et al. 2013

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MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types.

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Section: Resultsmentioning

confidence: 99%

MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

et al. 2013

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“…As pointed out by Carr et al [2011] in patients with deletions including the RASA1 gene located proximally to MEF2C , capillary or arterio-venous malformations or fistulae (CMs, AVMs, AVFs) should be expected. The RASA1 associated autosomal dominant CM-AVM-syndrome is characterized by multiple pink-red, round, or oval CMs mostly localized on the face and limbs increasing in number with age ( fig.…”

Section: Growth Parameters and Other Featuresmentioning

confidence: 99%

“…The RASA1 associated autosomal dominant CM-AVM-syndrome is characterized by multiple pink-red, round, or oval CMs mostly localized on the face and limbs increasing in number with age ( fig. 2 ) [Carr et al, 2011]. About 30% of affected individuals have associated AVMs and/or AVFs which are typically located in the head and neck region [Bayrak-Toydemir andStevenson, 1993-2011;Boon et al, 2005].…”

Section: Growth Parameters and Other Featuresmentioning

confidence: 99%

“…Both Zweier et al [2010] and Le Meur et al [2010] pointed out the phenotypic overlap to Rett syndrome, and Zweier et al [2010] demonstrated molecular interaction of the respective genes. Attributable to the wide use of molecular karyotyping or array comparative genomic hybridization, by now a total of 23 patients with 5q14.3q15 microdeletions have been reported [Cardoso et al, 2009;Engels et al, 2009;Berland and Houge, 2010;Le Meur et al, 2010;Novara et al, 2010;Nowakowska et al, 2010;Zweier et al, 2010;Carr et al, 2011;Mikhail et al, 2011;Tonk et al, 2011], but no further patients with point mutations, indicating that the phenotype is not well recognized. Sixteen microdeletions involved MEF2C and additional genes, 3 multi-gene microdeletions had a proximal breakpoint close to, but distally to MEF2C [Cardoso et al, 2009;Engels et al, 2009], and 4 microdeletions involved MEF2C only [Le Meur et al, 2010;Novara et al, 2010;Nowakowska et al, 2010;Mikhail et al, 2011].…”

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The MEF2C-Related and 5q14.3q15 Microdeletion Syndrome

Zweier

Rauch

2011

Mol Syndromol

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deletion also includes the RASA1 gene show features of the respective capillary and arterio-venous malformations and fistula syndrome. The phenotypic overlap with Rett syndrome is explained by a shared pathway and, accordingly, diminished MECP2 and CDKL5 expression is measureable in patients with MEF2C defects. Further research of this pathway may therefore eventually lead to a common therapeutic target.Copyright © 2012 S. Karger AG, Basel History of the SyndromeAs a result of joint efforts of the German Mental Retardation Network (MRNET) and the Decipher database, Engels, Firth and Rauch initiated a study on 5q14.3q15 microdeletions and delineated a novel syndrome characterized by severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies [Engels et al., 2009]. These deletions partially overlapped with the distally more extended deletions in 3 patients with severe mental retardation, seizures and periventricular heterotopia described by Cardoso et al. [2009]. The 1.6-Mb smallest region of overlap contained the neurodevelopmental LYSMD3 gene as Key Words MEF2C ؒ Microdeletion 5q14 ؒ Rett syndrome-like ؒ Seizures ؒ Severe intellectual disability ؒ Severe mental retardation Abstract Disorders related to the autosomal transcription factor MEF2C located in 5q14.3 were first described in 2009 and have since evolved to one of the more common microdeletion syndromes. Mutational screening in a larger cohort revealed heterozygous de novo mutations of MEF2C in about 1% of patients with moderate to severe intellectual disability, and the phenotype is similar in patients with intragenic deletions and multigenic microdeletions. Clinically, MEF2C -related disorders are characterized by severe intellectual disability with absent speech and limited walking abilities, hypotonia, seizures, and a variety of minor brain anomalies. The majority of patients show a similar facial gestalt with broad forehead, flat nasal bridge, hypotonic mouth, and small chin, as well as strabismus, but this phenotype is clinically not well recognized. The course of the disease is generally quite uniform, but patients with point mutations and smaller deletions seem to have a higher chance of walking skills and a lower risk of refractory seizures. Patients in whom the micro-

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“…[4][5][6][7] Brain structural abnormalities are common and include decreased white matter volume, periventricular heterotopia, and polymicrogyria. [10][11][12] The underlying genetics of 5q14.3 deletion epilepsy is complex. [10][11][12] The underlying genetics of 5q14.3 deletion epilepsy is complex.…”

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ADGRV1 is implicated in myoclonic epilepsy

et al. 2017

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Our data suggest that the ADGRV1 variation contributes to epilepsy with myoclonic seizures, although the inheritance pattern may be complex in many cases. In patients with 5q14.3 deletion and epilepsy, ADGRV1 haploinsufficiency likely contributes to seizure development. The latter is a shift from current thinking, as MEF2C haploinsufficiency has been considered the main cause of epilepsy in 5q14.3 deletion syndrome. In cases of 5q14.3 deletion and epilepsy, seizures likely occur due to haploinsufficiency of one or both of ADGRV1 and MEF2C.

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5q14.3 neurocutaneous syndrome: A novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C

Cited by 29 publications

References 19 publications

MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

The MEF2C-Related and 5q14.3q15 Microdeletion Syndrome

ADGRV1 is implicated in myoclonic epilepsy

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