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.

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

“…We report on the molecular and phenotypic spectrum of 36 individuals with sequence variants in SETD1B, representing the largest cohort reported to date. Previous work suggested a possible gain-of-function effect of pathogenic variants in SETD1B [14]; however, further reports [8,12,13,[15][16][17][18][19], including this work, point toward a loss-of-function mechanism. Clinical features of our cohort compared to previously reported individuals with a (likely) pathogenic SETD1B variant [8,[12][13][14][15] are provided in Table 2.…”

“…This indicates that SETD1B dysfunction severely impacts physiological neurodevelopment even in the absence of epilepsy, suggesting the condition is a developmental encephalopathy, with or without epilepsy. Previously alterations of SETD1B were mainly associated with myoclonic absences [13] and predominantly refractory epilepsy. Although myoclonic absence seizures were often observed in our cohort-confirming this association-other seizure types were regularly encountered at onset, including focal or generalized tonic-clonic seizures.…”

“…Consistent with this, pathogenic variants in SETD1B have been associated with a syndromic intellectual developmental disorder including seizures and language delay (IDDSELD, OMIM 619000). To date, clinical features have been described for 11 affected individuals with (likely) pathogenic SETD1B sequence variants [8,[12][13][14][15]. Individuals with microdeletions encompassing SETD1B have also been described [8,[16][17][18][19]; however, most of these deletions encompass additional genes making phenotypic comparisons challenging.…”

Delineating the molecular and phenotypic spectrum of theSETD1B-related syndrome

“…This work reports on the molecular and phenotypic spectrum of 36 individuals with sequence variants in SETD1B , representing the largest cohort reported to date. Previous work suggested a possible gain-of-function effect of pathogenic variants in SETD1B 14 , however, further reports 8,12,13, 15–19 including this work, point towards a loss-of-function mechanism. Clinical features of our cohort compared to the eleven previously reported individuals with a (likely) pathogenic SETD1B variant 8,12–15 is provided in Table 2.…”

“…This indicates that SETD1B dysfunction severely impacts physiological neurodevelopment even in the absence of epileptic activity, suggesting the condition is a developmental encephalopathy, with or without epilepsy. Previous work emphasized that alterations of SETD1B were mainly associated with myoclonic absences 13 and predominantly refractory epilepsy. Although myoclonic absence seizures were often observed in our cohort – confirming this association – also other seizure types were regularly encountered at onset, including focal or generalized tonic-clonic seizures.…”