Chromatin remodeling dysfunction extends the etiological spectrum of schizophrenia: a case report

Abstract

Background: The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. Case presentation: The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). Conclusions: This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.

Expanding the genetic and phenotypic spectrum of CHD2‐related disease: From early neurodevelopmental disorders to adult‐onset epilepsy

“…Hypsarrhythmia was reported in one patient with epileptic spasms (#82). Photosensitivity was reported in 45.6% patients with epilepsy (data available for n = 79/94, reported in 36/79): more specifically, both clinical and EEG photosensitivity was described in nine patients (Caputo et al, 2018; Chénier et al, 2014; Galizia et al, 2015; Thomas et al, 2015; Trivisano et al, 2015; Veredice et al, 2009), only clinical in eight (Carvill et al, 2013; Thomas et al, 2015), and only electrographic in two ( n = 2) (Chénier et al, 2014; Poisson et al, 2020). No further details are available for the remaining patients with reported photosensitivity ( n = 17).…”

“…Genetic inclusion criteria were gross deletions or duplications involving the CHD2 gene, and missense or truncating variants classified as pathogenic or likely pathogenic according to the guidelines of the ACMG (Allen et al, 2013; Angione et al, 2019; Appenzeller et al, 2014; Bernardo et al, 2017; Cabrera‐Salcedo et al, 2020; Caputo et al, 2018; Carvill et al, 2013; Chen et al, 2020; Chénier et al, 2014; Costain et al, 2019; Courage et al, 2014; Demos et al, 2019; Dhamija et al, 2011; Fitzgerald et al, 2015; Galizia et al, 2015; Hamdan et al, 2014; Jiao et al, 2019; Lebrun et al, 2017; Li et al, 2008; J. Liu et al, 2018; Lund et al, 2014, 2013; Monlong et al, 2018; O'Roak et al, 2014; Peng et al, 2019; Petersen et al, 2018; Pinto et al, 2014; Poisson et al, 2020; Rauch et al, 2012; Richards et al, 2015; Rim et al, 2018; Routier et al, 2019; Snoeijen‐Schouwenaars et al, 2019; Suls et al, 2013; Symonds et al, 2019; Thomas et al, 2015; Trivisano et al, 2015; Tsang et al, 2019; Veredice et al, 2009; Verhoeven et al, 2016; J. Wang et al, 2019; Y. Wang et al, 2017a, 2017b; Zhou et al, 2018; Ziats et al, 2020).…”

“…Epilepsy syndromes encompassed a wide range of presentations including epilepsy with myoclonic-atonic seizures (EMAS) (Caputo et al, 2018;Chénier et al, 2014;Galizia et al, 2015;Thomas et al, 2015;Trivisano et al, 2015;Veredice et al, 2009), only clinical in eight (Carvill et al, 2013;Thomas et al, 2015), and only electrographic in two (n = 2) (Chénier et al, 2014;Poisson et al, 2020). No further details are available for the remaining patients with reported photosensitivity (n = 17).…”

L1 Retrotransposons: A Potential Endogenous Regulator for Schizophrenia

“…However, the effects of chromatin remodeling in individual brain cell type and its association with L1 retrotransposition or schizophrenia is still a loop which needs further investigation. Chromodomain helicase DNA binding protein 2 (CHD2) gene is involved in neurogenesis, chromatin remodeling, and gene expression, and detrimental mutation in CHD2 has been found relevant to the onset of schizophrenia in children ( Poisson et al, 2020 ). However, the precise roles of CHD2 in L1 retrotransposition is yet to be established, which needs further investigation to delineate the mechanism for the treatment of schizophrenia.…”

The Value of a Comprehensive Genomic Evaluation in Prenatal Diagnosis of Genetic Diseases: A Retrospective Study

“…It is a fact that one or more types of pathogenic or likely pathogenic genetic variations may exist in an individual, such as SNVs, small insertions and deletions (InDels), and CNVs. Double diagnoses or autosomal recessive (AR) genetic diseases caused by CNVs, and SNV/InDels have been reported in many postpartum or prenatal studies [ 12 , 13 , 14 , 15 , 16 , 17 ]. In the current mainstream sequential procedure in prenatal diagnosis, cases with clinically significant CNVs detected by CMA would not be referred for ES, which may omit the possibility of identifying other underlying monogenic diseases.…”