Microdeletions ofELP4Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

Abstract

Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10(-3) , as well as for autism, P = 2.7 × 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

“…Finally, this study should be considered in the broader context of the requirement for the six-subunit Elongator complex in the CNS. Variants in the ELP2 gene are associated with neurodevelopmental (including intellectual) disability (Cohen et al, 2015; Franic et al, 2015) while ELP3 variants are associated with ALS (Simpson et al, 2009; Kwee et al, 2012), and loss of ELP4 can cause Rolandic epilepsy syndrome and intellectual disability (Strug et al, 2009; Nguyen et al, 2010; Gkampeta et al, 2014; Reinthaler et al, 2014; van Blitterswijk et al, 2014; Addis et al, 2015). This study adds to the growing understanding of the critical function for the Elongator complex in the CNS by revealing the repercussions of Ikbkap loss in the CNS.…”

“…Studies have demonstrated that tRNA from FD patients contains reduced levels of the modified wobble nucleoside mcm 5 s 2 U 34 (Lin et al, 2013; Karlsborn et al, 2014a; Yoshida et al, 2015), lending support to a direct function of IKAP in translation. Interestingly, three other Elongator subunits, ELP2 to ELP4 , have each been associated with CNS disorders (Nguyen et al, 2010): ELP2 and ELP4 have been implicated in intellectual development disorders (Cohen et al, 2015; Franic et al, 2015; Addis et al, 2015) and epilepsy (Gkampeta et al, 2014; Reinthaler et al, 2014; Strug et al, 2009), and ELP3 with amyotrophic lateral sclerosis (Simpson et al, 2009; Kwee et al, 2012). …”

Neural Stem Cells to Cerebral Cortex: Emerging Mechanisms Regulating Progenitor Behavior and Productivity

“…The Elongator complex, a histone acetyltransferase complex that associates directly with RNA polymerase II during transcriptional elongation, is required for proper generation of IPs in the developing cerebral cortex. Elongator is a macromolecular complex (Elp1-Elp6) expressed in the developing nervous system (Creppe et al, 2009) and mutations that decrease its function are associated with neurodegenerative diseases, such as ALS and familial dysautonomia (Anderson et al, 2001;Slaugenhaupt et al, 2001;Simpson et al, 2009) as well as intellectual disability and autism (Addis et al, 2015;Cohen et al, 2015). A role for this complex in the control of projection neuron migration and differentiation was through its acetylation of ␣-tubulin (Creppe et al, 2009).…”

Animal and cellular models of familial dysautonomia

“…The Elongator complex has also been shown to be required in the nucleus for normal transcript elongation [18, 19] and to negatively regulate exocytosis in yeast and C.elegans , and is required for vesicle trafficking, cytoskeleton stability and dynamics [20–26], and neuronal survival [27–29]. Interestingly, IKAP is just one of six subunits of the Elongator complex and recently it has become clear that several of the other Elongator genes are also associated with neurological disorders: ELP3 with amyotrophic lateral sclerosis, ELP2 and ELP4 with intellectual disability and ELP4 with Rolandic epilepsy [30–36]. …”