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De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences.

ABSTRACT: Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness. Here, we report an individual with epilepsy with myoclonic absences, mild intellectual disabilities, language disorder, and autism spectrum disorder. His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area. His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz spike-and-wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness. Using whole-exome sequencing, we found a novel de novo variant, c.386T>G, p.(Val129Gly), in SETD1B (SET domain containing 1B). We previously reported that two individuals with a de novo SETD1B variant showed intellectual disability, epilepsy, and autism. Of note, one of those individuals and the present case showed epilepsy with myoclonic absences. Therefore, this report supports the indication that SETD1B may be a causative gene for neurodevelopmental disorders and suggests that epilepsy with myoclonic absences may be a characteristic feature of SETD1B-related disorders.

SUBMITTER: Hiraide T

PROVIDER: S-EPMC6698685 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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De novo variants in <i>SETD1B</i> cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences.

Hiraide Takuya T Hattori Ayako A Ieda Daisuke D Hori Ikumi I Saitoh Shinji S Nakashima Mitsuko M Saitsu Hirotomo H

Epilepsia open 20190524 3

Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness. Here, we report an individual with epilepsy with myoclonic absences, mild intellectual disabilities, language disorder, and autism spectrum disorder. His interictal electroencephalogram revealed a spike-and-slow wave complex dominant in the frontal area. His ictal polygraphic and video-electroencephalogram showed a characteristic diffuse synchronous 3-Hz ...[more]

PMID: 31440728

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Project description:We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID), and/or epilepsy by whole exome sequencing. These variants, comprising two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman A, Thouta S, Mancini GM, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study; Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Am J Hum Genet 101: 65-74, 2017). Surprisingly, all eight missense variants resulted in gain of function (GOF) due to hyperpolarized voltage dependence of activation or slowed deactivation kinetics, whereas the two nonsense variants were confirmed to be loss of function (LOF). One severe GOF allele (P369T) was tested and found to extend a dominant GOF effect to heteromeric KCNQ5/3 channels. Clinical presentations were associated with altered KCNQ5 channel gating: milder presentations with LOF or smaller GOF shifts in voltage dependence [change in voltage at half-maximal conduction (ΔV50) = ∼-15 mV] and severe presentations with larger GOF shifts in voltage dependence (ΔV50 = ∼-30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created with CRISPR/Cas9. Both lines exhibited handling- and thermal-induced seizures and abnormal cortical EEGs consistent with epileptiform activity. Our study thus provides evidence for in vivo KCNQ5 LOF pathogenicity and strengthens the contribution of both LOF and GOF mutations to global pediatric neurological impairment, including ID/epilepsy.NEW & NOTEWORTHY Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental delay, intellectual disability, and/or epilepsy. Expression of these variants along with four previously reported KCNQ5 variants from a similar cohort revealed GOF potassium channels, negatively shifted in V50 of activation and/or delayed deactivation kinetics. GOF is extended to KCNQ5/3 heteromeric channels, making these the predominant channels affected in heterozygous de novo patients. Kcnq5 LOF mice exhibited seizures, consistent with in vivo pathogenicity.

Dataset Information

De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences.

Publications

De novo variants in <i>SETD1B</i> cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences.

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