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Clinics and Practice May 2024Tatton-Brown-Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the gene, which is an important participant in epigenetic...
Tatton-Brown-Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton-Brown-Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the , leading to the formation of a premature stop codon-NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton-Brown-Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the gene significantly increases the risk of developing acute myeloid leukemia.
PubMed: 38804405
DOI: 10.3390/clinpract14030073 -
JCI Insight Jan 2024Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27...
Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.
Topics: Animals; Mice; Osteogenesis; Fibroblasts; Polycomb Repressive Complex 2; Disease Models, Animal; Histone Demethylases
PubMed: 38015625
DOI: 10.1172/jci.insight.173392 -
The Journal of Clinical Endocrinology... Jan 2024Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature,... (Review)
Review
Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged. Multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome, respectively, variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.
Topics: Humans; Autism Spectrum Disorder; Abnormalities, Multiple; Syndrome; Histone Methyltransferases; Intellectual Disability; Epigenesis, Genetic
PubMed: 37450557
DOI: 10.1210/clinem/dgad420 -
BioRxiv : the Preprint Server For... Jun 2023Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in , which encodes the predominant H3K27...
Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in , which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, p.R684C. mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. mice had abnormal bone parameters indicative of skeletal overgrowth, and osteoblasts showed increased osteogenic activity. RNA-seq comparing osteoblasts differentiated from and bone marrow mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases Kdm6a/6b substantially reversed the excessive osteogenesis in cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state, and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.
PubMed: 37425751
DOI: 10.1101/2023.06.23.546270 -
Genetics Aug 2023EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3...
EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2 has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2 are homologous to fly Enhancer of zeste (E(z)), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WT induces homeotic patterning defects but notably the E(z)A691G variant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila.
Topics: Animals; Humans; Drosophila; Drosophila melanogaster; Enhancer of Zeste Homolog 2 Protein; Histones; Polycomb Repressive Complex 2
PubMed: 37314226
DOI: 10.1093/genetics/iyad110 -
MedRxiv : the Preprint Server For... Feb 2023( , a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes through modifying histone 3 lysine27 (H3K27) residues. represses...
( , a Polycomb Repressive Complex-2 (PRC2) component, is involved in a myriad of cellular processes through modifying histone 3 lysine27 (H3K27) residues. represses transcription of downstream target genes through H3K27 trimethylation (H3K27me3). Genetic mutations in histone modifiers have been associated with developmental disorders, while has not yet been linked to any human disease. However, the paralog is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a variant in , p.Ala678Gly, through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and was the best candidate variant found in the exome. Human / are homologous to fly , an essential gene in flies, and the residue (A678 in humans, A691 in ) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wild-type and the variant . The variant led to hyper H3K27me3 while the did not, suggesting this is as a gain-of-function allele. When expressed under the tubulin promotor the variant rescued null-lethality similar to wild-type but the flies exhibit bang sensitivity and shortened lifespan. In conclusion, here we present a novel variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in . Biochemically this allele leads to increased H3K27me3 suggesting gain-of-function, but when expressed in adult flies the has some characteristics of partial loss-of-function which may suggest it is a more complex allele .
PubMed: 36778246
DOI: 10.1101/2023.01.31.23285113 -
BMC Bioinformatics Sep 2022Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity...
BACKGROUND
Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of epigenetic features across this full range of epigenetic scale, making DNA methylation valuable for mapping regions of general epigenetic dysregulation. However, existing methods are unable to accurately identify regions of differential methylation across this full range of epigenetic scale directly from DNA methylation data.
RESULTS
To address this, we developed DMRscaler, a novel method that uses an iterative windowing procedure to capture regions of differential DNA methylation (DMRs) ranging in size from single basepairs to whole chromosomes. We benchmarked DMRscaler against several DMR callers in simulated and natural data comparing XX and XY peripheral blood samples. DMRscaler was the only method that accurately called DMRs ranging in size from 100 bp to 1 Mb (pearson's r = 0.94) and up to 152 Mb on the X-chromosome. We then analyzed methylation data from rare-disease cohorts that harbor chromatin modifier gene mutations in NSD1, EZH2, and KAT6A where DMRscaler identified novel DMRs spanning gene clusters involved in development.
CONCLUSION
Taken together, our results show DMRscaler is uniquely able to capture the size of DMR features across the full range of epigenetic scale and identify novel, co-regulated regions that drive epigenetic dysregulation in human disease.
Topics: Chromatin; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genome; Humans
PubMed: 36064314
DOI: 10.1186/s12859-022-04899-1 -
Stem Cell Reports Sep 2022Mutations in the embryonic ectoderm development (EED) cause Weaver syndrome, but whether and how EED affects embryonic brain development remains elusive. Here, we...
Mutations in the embryonic ectoderm development (EED) cause Weaver syndrome, but whether and how EED affects embryonic brain development remains elusive. Here, we generated a mouse model in which Eed was deleted in the forebrain to investigate the role of EED. We found that deletion of Eed decreased the number of upper-layer neurons but not deeper-layer neurons starting at E16.5. Transcriptomic and genomic occupancy analyses revealed that the epigenetic states of a group of cortical neurogenesis-related genes were altered in Eed knockout forebrains, followed by a decrease of H3K27me3 and an increase of H3K27ac marks within the promoter regions. The switching of H3K27me3 to H3K27ac modification promoted the recruitment of RNA-Pol2, thereby enhancing its expression level. The small molecule activator SAG or Ptch1 knockout for activating Hedgehog signaling can partially rescue aberrant cortical neurogenesis. Taken together, we proposed a novel EED-Gli3-Gli1 regulatory axis that is critical for embryonic brain development.
Topics: Animals; Brain; Epigenesis, Genetic; Hedgehog Proteins; Histones; Mice; Nerve Tissue Proteins; Neurogenesis; Polycomb Repressive Complex 2; Zinc Finger Protein GLI1; Zinc Finger Protein Gli3
PubMed: 35931079
DOI: 10.1016/j.stemcr.2022.07.004 -
Animal Genetics Oct 2022Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young-adult Australian Shepherd dogs...
Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young-adult Australian Shepherd dogs characterized by uncoordinated movements and spasticity, worsening progressively and leading to inability to walk. Pedigree analysis suggested an autosomal recessive transmission. By whole genome sequencing and variant filtering of an affected dog we identified a PNPLA8:c.1169_1170dupTT variant. This variant, located in PNPLA8 (Patatin Like Phospholipase Domain Containing 8), was predicted to induce a PNPLA8:p.(His391PhefsTer394) frameshift, leading to a premature stop codon in the protein. The truncated protein was predicted to lack the functional patatin catalytic domain of PNPLA8, a calcium-independent phospholipase. PNPLA8 is known to be essential for maintaining mitochondrial energy production through tailoring mitochondrial membrane lipid metabolism and composition. The Australian Shepherd ataxia shares molecular and clinical features with Weaver syndrome in cattle and the mitochondrial-related neurodegeneration associated with PNPLA8 loss-of-function variants in humans. By genotyping a cohort of 85 control Australian Shepherd dogs sampled in France, we found a 4.7% carrier frequency. The PNPLA8:c.[1169_1170dupTT] allele is easily detectable with a genetic test to avoid at-risk matings.
Topics: Animals; Australia; Cattle; Cattle Diseases; Dog Diseases; Dogs; Frameshift Mutation; Humans; Pedigree; Phospholipases; Spinocerebellar Degenerations
PubMed: 35864734
DOI: 10.1111/age.13245