Histones: coming of age in Mendelian genetic disorders

Abstract

Histones hold significant interest in development and genetic disorders due to their critical roles in chromatin dynamics, influencing gene expression and genome integrity. These roles are linked to alterations of post-translational marks, which are generally concentrated in the histone tails. The machinery modifying or interpreting these marks, known as chromatin writers, erasers or readers, have been associated with many Mendelian disorders; however, it has been only recently that the histone proteins themselves have been directly implicated in Mendelian conditions. High throughput sequencing has recently identified mutations in genes encoding histone H1, H3 and H4, all causing neurodevelopmental disorders with clinical variability. Notably, many of the mutations lie outside of recognised post-translational modification-associated residues, suggesting disrupting the core functions of histones is a primary molecular mechanism underpinning these neurodevelopmental phenotypes. In this review, we describe the clinical and genetic features of histone-related disorders, focusing on the unique aspects associated with each histone gene family, while noting the commonalities which provide insight into the required roles for histone fidelity in brain development and functioning.

NeuroTri2-VISDOT: An open-access tool to harness the power of second trimester human single cell data to inform models of Mendelian neurodevelopmental disorders

“…Germline variants in genes encoding histones are an emerging class of Mendelian NDDs 39 , which have recently been classified by OMIM. HIST1H1E syndrome/Rahman Syndrome (OMIM #617537) is caused by germline variants in the gene HIST1H1E/H1-4 which encodes the histone H1 linker protein.…”

“…We then apply NeuroTri2-VISDOT to the spectrum of syndromes categorized as Noonan Syndrome-like RASopathies, including Noonan Syndrome (NS) (OMIM #163950; #610733; #616559; #613224; #616564; #605275; #619745; #615355; #618624; #618499; #611553); NS with multiple lentigines (OMIM #151100); NS-like disorder with loose anagen hair (OMIM #607721, 617506); Cardiofaciocutaneous Syndrome (OMIM #115150, 615279, 615280); Costello Syndrome (OMIM #218040); CBL-related RASopathy (OMIM #613563); wide spectrum RASopathy (OMIM #615278, 609942); MAPK1-related RASopathy (OMIM # 619087); and newly described NS-like RASopathies caused by variants in CDC42 and YWHAZ 37,38 . Finally, we employ NeuroTri2-VISDOT to an emerging class of NDDs caused by germline variants in histone genes 6,39 . Using NeuroTri2-VISDOT, we demonstrate that single cell RNA sequencing data from the developing human brain can be used to motivate the evidence-based selection of relevant cell populations to explore the pathogenic mechanism underlying Mendelian NDDs.…”

“…37,38 . Finally, we employ NeuroTri2-VISDOT to an emerging class of NDDs caused by germline variants in histone genes 6,39 .…”