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SETD1B-Associated Neurodevelopmental Disorder

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SETD1B-Associated Neurodevelopmental Disorder Genotype- phenotype correlations J Med Genet: first published as 10.1136/jmedgenet-2019-106756 on 16 June 2020. Downloaded from Original research SETD1B- associated neurodevelopmental disorder Alexandra Roston ,1 Dan Evans,2 Harinder Gill,1,3 Margaret McKinnon,1 Bertrand Isidor,4 Benjamin Cogné ,4,5 Jill Mwenifumbo,1,6 Clara van Karnebeek,7,8 Jianghong An,9 Steven J M Jones,9 Matthew Farrer,2 Michelle Demos,10 Mary Connolly,10 William T Gibson ,1 CAUSES Study, EPGEN Study ► Additional material is ABSTRACT same gene allows causal inference for those geno- published online only. To view Background Dysfunction of histone methyltransferases type–phenotype correlations. This is especially true please visit the journal online (http:// dx. doi. org/ 10. 1136/ and chromatin modifiers has been implicated in complex when perturbation of the general biological process jmedgenet- 2019- 106756). neurodevelopmental syndromes and cancers. SETD1B has, in similar contexts, been shown reproducibly encodes a lysine- specific methyltransferase that assists to result in similar phenotypes. For numbered affiliations see in transcriptional activation of genes by depositing Individual case reports have appeared in the end of article. H3K4 methyl marks. Previous reports of patients with literature describing neurodevelopmental delays rare variants in SETD1B describe a distinctive phenotype associated with rare coding variants in SETD1B, Correspondence to Dr Alexandra Roston, that includes seizures, global developmental delay and and with hemizygosity for SETD1B due to CNVs. Department of Medical intellectual disability. Here we show that pathogenic variants within Genetics, The University of Methods Two of the patients described herein were SETD1B contribute to a conserved phenotype that British Columbia, Vancouver, BC identified via genome-wide and exome-wide testing, includes intellectual disability and childhood- onset, V6T 1Z4, Canada; with microarray and research- based exome, through treatment- refractory seizures. alexandra. roston@ phsa. ca the CAUSES (Clinical Assessment of the Utility of SETD1B encodes the protein SET domain- Received 5 December 2019 Sequencing and Evaluation as a Service) Research containing protein 1B, a lysine- specific methyltrans- Revised 11 March 2020 Clinic at the University of British Columbia. The third ferase involved in histone methylation.1 Working in Accepted 14 April 2020 Vancouver patient had clinical trio exome sequencing close association with four other subunits, SETD1B Published Online First 16 June 2020 through Blueprint Genetics. The fourth patient underwent forms the catalytic component of a COMPASS singleton exome sequencing in Nantes, with subsequent (Complex Proteins Associated with Set1) histone recruitment to this cohort through GeneMatcher. modifier, methylating histone H3 at Lys4 up to Results Here we present clinical reports of four patients three times.1 2 This trimethylated histone mark is with rare coding variants in SETD1B that demonstrate believed to assist in the transcriptional activation of a shared phenotype, including intellectual disability, nearby genes. Thus, SETD1B is an epigenetic writer language delay, conserved musculoskeletal findings and that modifies chromatin structure, with down- 2 seizures that may be treatment- refractory. We include stream effects on gene expression. http://jmg.bmj.com/ supporting evidence from next- generation sequencing Previous reports by Hiraide et al and Den et al among a cohort of paediatric patients with epilepsy. described four Japanese patients, aged 1, 7, 10 and Conclusion Rare coding variants in SETD1B can 34 years, whose phenotypes included intellectual cause a diagnosable syndrome and could contribute disability, seizures and autistic features.3–5 All of as a risk factor for epilepsy, autism and other these patients also had craniofacial, musculoskeletal neurodevelopmental phenotypes. In the long term, some and cutaneous abnormalities. patients may also be at increased risk for cancers and Published reports of patients with microdeletions on September 24, 2021 by guest. Protected copyright. other complex diseases. Thus, longitudinal studies are encompassing SETD1B document similar pheno- required to further elucidate the precise role of SETD1B types. Three affected patients had seizures, and one in neurodevelopmental disorders and other systemic had moderate- severe intellectual disability.6–8 Addi- disease. tional findings included receptive and expressive language disorders as well as motor delays.6–8 Most recently, Krzyzewska et al9 described a specific DNA hypermethylation signature believed to be INTRODUCTION associated with SETD1B loss of function, which was Protein- altering variants in histone methyltransfer- used to reclassify two SETD1B variants of uncertain ases, and in chromatin modifiers more generally, significance (VUS) as pathogenic. have been implicated in complex neurodevelop- Here we present detailed descriptions of four mental syndromes and in cancers. Neurodevelop- additional patients, along with rare SETD1B alleles © Author(s) (or their mental syndromes associated with these variants identified in a cohort of patients with epilepsy. The employer(s)) 2021. No are typically dominant and occur sporadically due de novo variants in SETD1B are as follows: a splice- commercial re- use. See rights to de novo pathogenic mutations. Parent- to- child site variant c.5589+1G>A (p.?), nonsense variants and permissions. Published transmission of these variants occurs rarely, often c.2932C>T: p.(Gln978Ter) and c.3964C>T p. by BMJ. due to parents having somatic or gonadal mosa- (Gln1322Ter), and a missense variant c.5833T>C p. To cite: Roston A, Evans D, icism for the mutation. The presence of three inde- (Phe1945Leu). Our replication study consisted Gill H, et al. J Med Genet pendent families in which the same rare phenotype of comparing the number of rare coding variants 2021;58:196–204. associates with different de novo mutations in the in SETD1B identified in a sequentially recruited 196 Roston A, et al. J Med Genet 2021;58:196–204. doi:10.1136/jmedgenet-2019-106756 Genotype- phenotype correlations J Med Genet: first published as 10.1136/jmedgenet-2019-106756 on 16 June 2020. Downloaded from cohort of 207 children and adults with childhood- onset epilepsy, support the existence of an RNA recognition motif, an lysine- with the number of SETD1B variants of similar or lower minor specific histone demethylase (LSD) motif, a coiled-coil domain, allele frequency (MAF) found among a heterogeneous cohort an N- SET domain containing a WDR5 interacting motif, a SET of patients with neurological disorders excluding epilepsy. In domain and a post- SET domain (figure 1, online supplementary the context of previously reported cases, these patients confirm figure S1 and table S1).1 13–17 Domain boundaries are listed in the implication of rare SETD1B variants in paediatric epilepsy online supplementary table S1. We then tallied domain- specific and confirm a shared phenotype produced by some de novo, allele frequencies observed in the EPGEN database (online highly penetrant variants. This phenotype includes intellectual supplementary table S2), among neurogenetic patients without disability, language delay, conserved musculoskeletal findings epilepsy, and in gnomAD controls (online supplementary table and seizures that may be treatment-refractory . S3). We summed variant counts across the specified domain for each variant type (missense single nucleotide variant, splice site, METHODS total). OR calculations are based off of the total number of vari- Individuals underwent whole genome or exome sequencing ants in each subclass, and on either the participant total (for the through several studies and diagnostic laboratories, including EPGEN and non- EPGEN neurological cohorts) or the median the CAUSES study (Clinical Assessment of the Utility of number of individuals as counted across the entire gene (control Sequencing and Evaluation as a Service), Blueprint Genetics, the gnomAD population). Service de Génétique Médicale in Nantes and EPGEN (Epilepsy To further investigate the possibility that rare pLoF variants Genetics Study).10–12 Analysis methods for these services have observed in paediatric- onset disease had different properties been detailed previously.10 11 In brief, individuals 1 and 2 had than rare variants observed among gnomAD participants, we trio genome sequencing through CAUSES, a study assessing the manually curated the 14 variants annotated as pLoF (in gnomAD application of exome sequencing as a hospital-based service. entry V.2.1.1) and compared these with the SETD1B variants Individual 3 had clinical trio exome sequencing (Whole Exome downloadable from the gnomAD participants listed as controls. Family Plus), through Blueprint Genetics in Helsinki, Finland. Three- dimensional modelling (online supplementary figure S2) Individual 4 underwent clinical exome sequencing with variant was based on the crystal structure of the MLL1 SET domain confirmation via Sanger sequencing in Nantes, France. as described previously.18–20 Tissue- specific expression (online Given the emerging association between rare coding SETD1B supplementary figure S3) was obtained from GTEx Analysis variants and epilepsy, variant lists derived from Vancouver’s Release V.8 ( gtexportal. org) by searching for the HUGO Gene EPGEN study database were queried as a replication set.11 Nomenclature Committee (HGNC) gene symbol SETD1B.21 Crude ORs were estimated
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