Whole‐exome sequencing and adrenocorticotropic hormone therapy in individuals with infantile spasms

Abstract

ABBREVIATIONS ACTHAdrenocorticotropic hormone CNV Copy number variant DEE Developmental and epileptic encephalopathy P/LP Pathogenic or likely pathogenic variant VUS Variants of uncertain significance WES Whole-exome sequencing AIM To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms.METHOD Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease. RESULTSLikely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology.INTERPRETATION This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. Highpriority candidates were identified in an additional five individuals. WES provides additional support for previously described disease-associated genes and expands their already broad mutational and phenotypic spectrum.

Infantile epileptic spasm syndrome as a new NR2F1 gene phenotype

“…A literature search done on the China National Knowledge Infrastructure (CNKI), Wanfang and PubMed databases using ‘NR2F1’ as the search term retrieved 16, 21 and 351 articles, respectively. After excluding irrelevant articles based on titles and content, 11 articles, which involved 13 cases of IESS associated with NR2F1, remained (Table 1) (Bertacchi et al, 2020; Chen et al, 2016; Demarest et al, 2022; Dimassi et al, 2016; Engels et al, 2009; Hino‐Fukuyo, 2015, p. 1; Hino‐Fukuyo, 2017; Kaiwar et al, 2017; Michaud et al, 2014; Rech et al, 2020).…”

“…Infantile epileptic spasm syndrome (IESS), which includes West syndrome (Zuberi et al, 2022), affects about 20 out of 100,000 live births. IESS is characterized by epileptic spasms between the age of 1 month and 2 years (Demarest et al, 2022; Dimassi et al, 2016). Infants with IESS often have developmental delays and developmental stagnation or regression at the onset of epileptic spasms.…”

“…Although metabolic and infectious factors rarely cause IESS, they are important contributors to its occurrence. Additionally, about a third of affected children have no identifiable causes, and genetic pathogenetic variants are thought to underlie such cases (Demarest et al, 2022).…”

“…2 years (Demarest et al, 2022;Dimassi et al, 2016). Infants with IESS often have developmental delays and developmental stagnation or regression at the onset of epileptic spasms.…”

Knockdown ofNeuroD2leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in aXenopus laevistadpole model of DEE75

“…Here, we show that even a relatively small decrease in functional NeuroD2 results in a detectable C-SC phenotype. The two original DEE-75 variants, Glu130Gln and Met134Tyr, are predicted to alter DNA binding (S ega et al 2019), and both have been linked to DEE in at least one other patient (R unge et al 2021; D emarest et al 2022; S akpichaisakul et al 2022). However a third variant in the DNA binding domain, Arg129Trp, was identified in a patient with neurodevelopmental delay but no epilepsy (R unge et al 2021).…”