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. 2021 Dec;63(12):1441-1447.
doi: 10.1111/dmcn.14989. Epub 2021 Jul 11.

Genetic convergence of developmental and epileptic encephalopathies and intellectual disability

Gemma L Carvill  1   2   3 , Sandra Jansen  4 , Amy Lacroix  5 , Matthew Zemel  5 , Michele Mehaffey  5 , Petra De Vries  4 , Han G Brunner  4   6 , Ingrid E Scheffer  7 , Bert B A De Vries  4 , Lisenka E L M Vissers  4 , Heather C Mefford  5   8
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Free article

Genetic convergence of developmental and epileptic encephalopathies and intellectual disability

Gemma L Carvill et al. Dev Med Child Neurol. 2021 Dec.
Free article

Abstract

Aim: To determine whether genes that cause developmental and epileptic encephalopathies (DEEs) are more commonly implicated in intellectual disability with epilepsy as a comorbid feature than in intellectual disability only.

Method: We performed targeted resequencing of 18 genes commonly implicated in DEEs in a cohort of 830 patients with intellectual disability (59% male) and 393 patients with DEEs (52% male).

Results: We observed a significant enrichment of pathogenic/likely pathogenic variants in patients with epilepsy and intellectual disability (16 out of 159 in seven genes) compared with intellectual disability only (2 out of 671) (p<1.86×10-10 , odds ratio 37.22, 95% confidence interval 8.60-337.0).

Interpretation: We identified seven genes that are more likely to cause epilepsy and intellectual disability than intellectual disability only. Conversely, two genes, GRIN2B and SCN2A, can be implicated in intellectual disability without epilepsy; in these instances intellectual disability is not a secondary consequence of ongoing seizures but rather a primary cause. What this paper adds A subset of genes are more commonly implicated in epilepsy than other neurodevelopmental disorders. GRIN2B and SCN2A are implicated in intellectual disability and epilepsy independently.

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References

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    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th edn. Washington, DC: American Psychiatric Association, 2013.
    1. Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet 2016; 17: 9-18.
    1. Heyne HO, Singh T, Stamberger H, et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet 2018; 50: 1048-53.
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    1. Mullen SA, Carvill GL, Bellows S, et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 2013; 81: 1507-14.

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