Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features

Abstract

The Polycomb group (PcG) gene RNF2 (RING2) encodes a catalytic subunit of the Polycomb Repressive Complex 1 (PRC1), an evolutionarily conserved machinery that post-translationally modifies chromatin to maintain epigenetic transcriptional repressive states of target genes including Hox genes. Here, we describe two individuals, each with rare de novo missense variants in RNF2. Their phenotypes include intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Population genomics data suggest that RNF2 is highly constrained for loss-of-function (LoF) and missense variants, and both p.R70H and p.S82R variants have not been reported to date. Structural analyses of the two alleles indicate that these changes likely impact the interaction between RNF2 and BMI1, another PRC1 subunit, or its substrate Histone H2A, respectively. Finally, we provide functional data in Drosophila that these two missense variants behave as LoF alleles in vivo. The evidence provide support for deleterious alleles in RNF2 being associated with a new and recognizable genetic disorder. This tentative gene-disease association in addition to the 12 previously identified disorders caused by PcG genes attests to the importance of these chromatin regulators in Mendelian disorders.

Dominant-negative mutations inCBX1cause a neurodevelopmental disorder

“…10 The PRC1.6 complex includes RNF2 , is mutated in Luo-Schoch-Yamamoto syndrome. 11 All these syndromes are characterized by developmental delay, intellectual disability, and autistic features, similar to those seen in individuals with CBX1 mutations. Therefore, disruption of this common molecular pathway may underlie the neurocognitive impairment seen in individuals with CBX1, EHMT1, ZNF462 , and RNF2 mutations.…”

“…Among these, genetic variants in HP1-interacting proteins represent an important class of neurodevelopmental disorders, including Kleefstra syndrome due to EHMT1 mutations, 6,7 Sifrim-Hitz-Weiss syndrome due to CHD4 mutations, 8 Helsmoortel-van der Aa syndrome due to ADNP mutations, 9 Weiss-Kruszka syndrome due to ZNF462 mutations, 10 and Luo-Schoch-Yamamoto syndrome due to RNF2 mutations. 11 All of these syndromes are associated with developmental delay and intellectual disability, suggesting the importance of HP1-interacting proteins in normal neurocognitive development. Although HP1β participates in the regulation of brain development, 12 dysfunction of the HP1 protein itself has not until now been associated with human neurocognitive disorders.…”

Intellectual disability-associated disruption of O-GlcNAc cycling impairs habituation learning in Drosophila

“…It is not known whether the regulation of PcG activity by sxc/OGT is important for cognitive function, but it can be noted that a series of PcG genes are associated with ID [80,81], and some of them are subject to regulation by OGT in the context of development or cancer. These include PHC1 -human ortholog of Drosophila Ph [82], RING1B (Drosophila Sce) [83,84], EZH2 (Drosophila E(z)) [85][86][87], YY1 (Drosophila pho) [88,89] and ASXL1 (Drosophila Asx) [90,91]. In addition, OGT regulates expression of PcG genes by O-GlcNAcylation of PcG transcriptional regulators, for example ATN1 (Drosophila Gug), which was identified in the embryonic O-GlcNAc proteome [60].…”

RING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis.

“…Phenotypes, even lethal ones, that did not display overt skeletal homeotic transformations highlight the plethora of cellular processes impacted by polycomb mechanisms. Widespread use of research and clinical exome sequencing is identifying rare de novo dominant missense variants in PRC1 components that are revealing an additional layer of complexity to our understanding of PRC1 genetic and functional mechanisms [9][10][11][12][13][14][15][16][17].…”