Molecular and clinical aspects of histone-related disorders

Abstract

Epigenetics is the coordination of gene expression without alterations in the DNA sequence. Epigenetic gene expression is regulated by an intricate system that revolves around the interaction of histone proteins and DNA within the chromatin structure. Histones remain at the core of the epigenetic gene transcription regulation where histone proteins, along with the histone modification enzymes, and the subunits of chromatin remodelers and epigenetic readers play essential roles in regulating gene expression. Histone-related disorders encompass the syndromes induced by pathogenic variants in genes encoding histones, genes encoding histone modification enzymes, and genes encoding subunits of chromatin remodeler and epigenetic reader complexes. Defects in genes encoding histones lead to the expression of abnormal histone proteins. Abnormalities in genes encoding histone modification enzymes result in aberrant histone modifications. Defects in genes encoding subunits of the chromatin remodeler complexes result in defective chromatin remodeling. Defects in genes that code for the epigenetic readers (bromodomain proteins) will hinder their ability to regulate gene transcription. These disorders typically present manifestations that impact the nervous system which is particularly sensitive due to its need for specific patterns of gene expression for neural cell function and differentiation. To date, 72 histone-related disorders have been described including 7 syndromes due to defects in histone genes, 35 syndromes due to histone modifications defects, 26 syndromes due to defects in chromatin remodeling, and 4 due to defects in epigenetic readers. In this review article, the molecular basis of histone structure and function is first explained, followed by a summary of the histone-related syndromes.

Keywords: Bromodomain proteins; Chromatin access; Chromatin remodeling; Epigenetic readers; Histone acetylation; Histone genes; Histone methylation; Histone modification; Nucleosome assembly; Nucleosome editing.

Fig. 1

Disorders of histone methylation and histone demethylation. A diagram presenting different syndromes associated with deficiencies of histone methyltransferases (left) and histone demethylases (right). NDD: neurodevelopmental disorder; IDD: intellectual developmental disorder

Fig. 2

Disorders of histone acetylation and histone deacetylation. A diagram presenting different syndromes associated with deficiencies of histone acetyltransferases (left) and histone deacetylases (right)

Fig. 3

Disorders of chromatin remodeling. A diagram presenting syndromes associated with defects in chromatin organization (CHD remodelers) (top left), syndromes associated with defects in chromatin access (SWI/SNF remodelers) (right), and syndromes associated with defects in chromatin editing (INO80 remodelers) (bottom left)

Fig. 4

Intra-syndrome facial phenotype similarity. A bar plot presenting intra-group cosine similarity between facial phenotype descriptors for histone-related syndromes, including sample size information (n). Darker green values correspond to larger sample sizes. Top 10 syndromes with the highest intra-group similarity: IDDAM, Stolerman, Bryant, IDDSSAD, Rahman, NEDSID, Snijders, CHARGE, Kleefstra, and Wiedemann. (ArboledA: Arboleda–Tham syndrome; ATRX: Alpha-thalassemia/impaired intellectual development syndrome; BIS: Blepharophimosis- impaired intellectual development syndrome; Bryant: Bryant–Li–Bhoj neurodevelopmental syndrome; Claes: Claes–Jensen syndrome; Coffin: Coffin–Siris syndrome; Cornelia: Cornelia De Lange syndrome; Diets: Diets–Jongmans syndrome; DYT: Childhood-onset dystonia 28; Floating: Floating-Harbor syndrome; HH5: Hypogonadotropic hypogonadism 5 with or without anosmia; IDDAM: Intellectual development disorder with autism and macrocephaly; IDDSELD: Intellectual development disorder with seizures and language delay; IDDSSAD: Intellectual developmental disorder with severe speech and ambulation defects; Luscan: Luscan Lumish syndrome; Menke: Menke–Hennekam syndrome; NEDSID: Neurodevelopmental disorder with speech impairment and dysmorphic facies; Rauch: Rauch–Steindl syndrome; Rubinstein: Rubinstein–Taybi syndrome; Say: Barber Say syndrome; Siderius: Siderius X-linked intellectual developmental disorder; Sifrim: Sifrim–Hitz-Weiss syndrome; Snijders: Snijders Blok–Campeau syndrome; Stolerman: Stolerman neurodevelopmental syndrome; Suleiman: Suleiman–El-Hattab syndrome; Tessadori: Tessadori-Van Haaften neurodevelopmental syndrome; Wiedemann: Wiedemann–Steiner syndrome)

Fig. 5

Inter-syndrome facial phenotype similarity. A syndrome Pairwise Comparison Matrix (sPCM), presenting inter-group cosine similarity between facial phenotype descriptors for histone-related syndromes. Darker green values correspond to a higher similarity in facial phenotypic features between the two syndromes. The sPCM diagonal shows a similarity of 1 when each syndrome is compared to itself. Top 10 syndrome pairs with highest inter-group similarity: Say-Weaver, Rauch-Say, CHARGE-Say, Cornelia-Luscan, Kleefstra-Rahman, Kleefstra-Stolerman, Say-Tessadori, DYT-Say, Kleefstra-Luscan, Luscan-Say. (ArboledA: Arboleda–Tham syndrome; ATRX: Alpha-thalassemia/impaired intellectual development syndrome; BIS: Blepharophimosis- impaired intellectual development syndrome; Bryant: Bryant–Li–Bhoj neurodevelopmental syndrome; Claes: Claes–Jensen syndrome; Coffin: Coffin–Siris syndrome; Cornelia: Cornelia De Lange syndrome; Diets: Diets–Jongmans syndrome; DYT: Childhood-onset dystonia 28; Floating: Floating-Harbor syndrome; HH5: Hypogonadotropic hypogonadism 5 with or without anosmia; IDDAM: Intellectual development disorder with autism and macrocephaly; IDDSELD: Intellectual development disorder with seizures and language delay; IDDSSAD: Intellectual developmental disorder with severe speech and ambulation defects; Luscan: Luscan Lumish syndrome; Menke: Menke–Hennekam syndrome; NEDSID: Neurodevelopmental disorder with speech impairment and dysmorphic facies; Rauch: Rauch–Steindl syndrome; Rubinstein: Rubinstein–Taybi syndrome; Say: Barber Say syndrome; Siderius: Siderius X-linked intellectual developmental disorder; Sifrim: Sifrim–Hitz-Weiss syndrome; Snijders: Snijders Blok–Campeau syndrome; Stolerman: Stolerman neurodevelopmental syndrome; Suleiman: Suleiman–El-Hattab syndrome; Tessadori: Tessadori-Van Haaften neurodevelopmental syndrome; Wiedemann: Wiedemann–Steiner syndrome)