Pathogenic variants in chromatin-related genes: Linking immune dysregulation to neuroregression and acute neuropsychiatric disorders

Abstract

We report eight children with de novo pathogenic DNA variants in chromatin-related genes: MORC2, CHD7, KANSL1, KMT2D, ZMYND11, HIST1HIE, EP300, and KMT2B. All children experienced infection or vaccine-provoked neuroregression or abrupt-onset neuropsychiatric syndromes. Most had delayed development (n = 6) before the first regression, and four had immune deficiency or autoimmunity (n = 4). At a mean age of 4 years 2 months (range 1-8 years), symptoms included infection-provoked autistic/language regression (n = 6), cognitive decline (n = 3), gait deterioration (n = 3), or abrupt-onset anxiety, obsessive-compulsive disorder, and/or tics (n = 5). Three children had ongoing infection-provoked deteriorations. Six children benefited from intravenous immunoglobulin (n = 3) or antibiotics (n = 4). Ribonucleic acid expression of the eight chromatin genes was similar in neuronal, glial, and peripheral leukocytes, unlike non-chromatin neurodevelopmental genes, which have predominantly neuronal expression. These cases demonstrate the role of chromatin dysregulation in autistic regression and abrupt-onset neuropsychiatric syndromes, potentially related to brain and immune gene dysregulation.

FIGURE 1

Immune and neuronal cell types contain chromatin machinery in the cell nucleus. Chromatin machinery influences how DNA is ‘wrapped’ around histones in the nucleosome: modifications such as writers, erasers, readers, and remodellers influence whether chromatin is closed (heterochromatin) and therefore less available for gene transcription mediated by polymerases such as RNAPII, or open (euchromatin) and therefore more available for gene transcription. Variations in chromatin‐related genes can affect gene transcription and downstream cellular function of both immune and neuronal cells, which may render them more vulnerable to environmental triggers such as infection.

FIGURE 2

Normalized transcripts per million values from proteinatlas.org using single‐cell ribonucleic acid (RNA) sequencing data sets are presented for each gene, for neuronal cells (excitatory and inhibitory) in black, glial cells (astrocyte, oligodendrocyte, and microglia) in grey, and peripheral leukocytes (T cell, B cell, granulocyte, and monocyte) in white. The chromatin genes (MORC2, CHD7, KANSL1, KMT2D, ZMYND11, HIST1H1E, EP300, KMT2B) reveal generally equal expression across neuronal, glial, and peripheral blood cell types, whereas selected non‐chromatin neurodevelopmental genes (GRIN2B, SHANK3, CDKL5, SCN1A) reveal RNA expression predominantly in neuronal and glial cells.