A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

Muona, Mikko; Berkovic, Samuel F.; Dibbens, Leanne M.; Oliver, Karen; Maljevic, Snezana; Bayly, Marta A.; Joensuu, Tarja; Canafoglia, Laura; Franceschetti, Silvana; Michelucci, Roberto; Markkinen, Salla; Heron, Sarah E.; Hildebrand, Michael S.; Andermann, Eva; Andermann, Frédérick; Gambardella, Antonio; Tinuper, Paolo; Bisulli, Francesca; Scheffer, Ingrid E.; Criscuolo, Chiara; Filla, Alessandro; Ferlazzo, Edoardo; Ahmad, Jamil; Ahmad, Adeel; Baykan, Betül; Said, Edith; Topçu, Meral; Riguzzi, P.; King, Mary D.; Özkara, Çiğdem; Andrade, Danielle M.; Engelsen, Bernt A.; Crespel, Arielle; Lindenau, Matthias; Lohmann, Ebba; Saletti, Veronica; Massano, João; Privitera, Michael; Espay, Alberto J.; Kauffmann, Brice; Duchowny, Michael; Møller, Rikke S.; Straussberg, Rachel; Afawi, Zaid; Ben‐Zeev, Bruria; Samocha, Kaitlin E.; Daly, Mark J.; Petrou, Steven; Lerche, Holger; Palotie, Aarno; Lehesjoki, Anna Elina

doi:10.1038/ng.3144

Cited by 262 publications

(281 citation statements)

References 79 publications

(86 reference statements)

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“…34 An unexpected observation for an established gene was made in a consanguineous Arab Israeli family comprising 6 affected siblings with a clinical pattern of epilepsy with myoclonic atonic seizures associated with borderline to moderate intellectual impairment and a first cousin with normal intellect and electroclinically mixed generalized and occipital seizures. CT scans in affected family members were unremarkable.…”

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confidence: 99%

Multiplex families with epilepsy

et al. 2016

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Objective: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis.Methods: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate.Results: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. Conclusion:A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies. Neurology ® 2016;86:713-722 GLOSSARY BECTS 5 benign childhood epilepsy with centrotemporal spikes; CNV 5 copy number variant; FS 5 febrile seizures; FTLE 5 familial temporal lobe epilepsy; GEFS1 5 genetic epilepsy with febrile seizures plus; GGE 5 genetic generalized epilepsy; IPOE 5 idiopathic photosensitive occipital epilepsy; JME 5 juvenile myoclonic epilepsy.Early epilepsy gene discoveries used the strategy of ascertaining very large families, where the family history supported the presence of simple inheritance, and success utilizing parametric linkage analysis was likely.

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Multiplex families with epilepsy

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“…Laforin and Malin genes were evaluated despite absence of Lafora bodies in the skin biopsy, relatively mild course, and lack of prominent mental findings; no mutation was detected. Although the ophthalmologic evaluation was within normal limits, a NEU1 mutation leading to c.914G>A and c625delG protein variation was detected in the genetic evaluation, which was performed in Finland (5). A change in c625delG was previously defined in the same codon and was reported as pathogenic (6).…”

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Progressive Myoclonic Epilepsy and NEU1 Mutation: A Different Phenotypic Case

Yavuz¹,

Altıokka²,

Matur³

et al. 2016

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Sialidosis are autosomal recessive inherited disorders caused by a mutation on the NEU1 gene. In type 1 sialidosis, a "cherry-red spot" can be observed in fundoscopic examinations. In this study, a woman aged 37 years without "cherry-red spot" on ophthalmologic examination is reported to draw attention to a new phenotypic variation. Although an ophthalmologic examination was normal, for patients with consanguineous parents with progressive ataxia, drug-resistant epilepsy and myoclonus must be investigated for progressive myoclonic epilepsy and genetic analysis for sialidosis must be performed. The diagnosis is also crucial for genetic consultancy of the family.

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“…Similar to our own experiences, the more recent NGS studies -including patients without preceding molecular investigations − provide a molecular diagnosis for~30% of the investigated epilepsy patients. 12,13 Setting up NGS gene identification studies…”

Section: Ngs Findings In Mendelian Epilepsy Disordersmentioning

confidence: 99%

Lessons learned from gene identification studies in Mendelian epilepsy disorders

et al. 2015

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Next-generation sequencing (NGS) technologies are now routinely used for gene identification in Mendelian disorders. Setting up cost-efficient NGS projects and managing the large amount of variants remains, however, a challenging job. Here we provide insights in the decision-making processes before and after the use of NGS in gene identification studies. Genetic factors are thought to have a role in~70% of all epilepsies, and a variety of inheritance patterns have been described for seizure-associated gene defects. We therefore chose epilepsy as disease model and selected 35 NGS studies that focused on patients with a Mendelian epilepsy disorder. The strategies used for gene identification and their respective outcomes were reviewed. High-throughput NGS strategies have led to the identification of several new epilepsy-causing genes, enlarging our knowledge on both known and novel pathomechanisms. NGS findings have furthermore extended the awareness of phenotypical and genetic heterogeneity. By discussing recent studies we illustrate: (I) the power of NGS for gene identification in Mendelian disorders, (II) the accelerating pace in which this field evolves, and (III) the considerations that have to be made when performing NGS studies. Nonetheless, the enormous rise in gene discovery over the last decade, many patients and families included in gene identification studies still remain without a molecular diagnosis; hence, further genetic research is warranted. On the basis of successful NGS studies in epilepsy, we discuss general approaches to guide human geneticists and clinicians in setting up cost-efficient gene identification NGS studies.

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A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

Cited by 262 publications

References 79 publications

Multiplex families with epilepsy

Multiplex families with epilepsy

Progressive Myoclonic Epilepsy and NEU1 Mutation: A Different Phenotypic Case

Lessons learned from gene identification studies in Mendelian epilepsy disorders

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