Weaver Syndrome Research Articles

Intrauterine growth in chromatinopathies: A long road for better understanding and for improving clinical management.

Chromatinopathies are a heterogeneous group of genetic disorders caused by pathogenic variants in genes coding for chromatin state balance proteins. Remarkably, many of these syndromes present unbalanced postnatal growth, both under- and over-, although little has been described in the literature. Fetal growth measurements are common practice in pregnancy management and values within normal ranges indicate proper intrauterine growth progression; on the contrary, abnormalities in intrauterine fetal growth open the discussion of possible pathogenesis affecting growth even in the postnatal period. Among the numerous chromatinopathies, we have selected six of the most documented in the literature offering evidence about two fetal overgrowth (Sotos and Weaver syndrome) and four fetal undergrowth syndromes (Bohring Opitz, Cornelia de Lange, Floating-Harbor, and Meier Gorlin syndrome), describing their molecular characteristics, maternal biochemical results and early pregnancy findings, prenatal ultrasound findings, and postnatal characteristics. To date, the scarce data in the literature on prenatal findings are few and inconclusive, even though these parameters may contribute to a more rapid and accurate diagnosis, calling for a better and more detailed description of pregnancy findings.

A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition.

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.

A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster.

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.

Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder.

The SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively. Clinical manifestations of these syndromes significantly overlap, although their different prevalence rates have recently been noted: generalized overgrowth, intellectual disability, scoliosis, and excessive loose skin appear to be less prevalent in IMMAS than in the other two syndromes. We could not determine any apparent genotype-phenotype correlation in IMMAS. The phenotype of neurofibromatosis type 1 arising from NF1 deletion was also shown to be modified by the deletion of SUZ12, 560 kb away. This review deepens our understanding of the clinical and genetic characteristics of IMMAS together with other overgrowth syndromes related to PRC2. We also report on a novel IMMAS patient carrying a splicing variant (c.1023+1G>C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.

First Korean Case of Weaver Syndrome Along with Neuroblastoma and Genetic Confirmation of EZH2 Variant

Inseong Oh, M.D., Boram Kim, M.D., Jee-Soo Lee, M.D., Man Jin Kim, M.D., Sung Im Cho, M.T., Sung Sup Park, M.D., Moon-Woo Seong, M.D.. Lab Med Online 2023;13:48-52. https://doi.org/10.47429/lmo.2023.13.1.48

Generation of DNA Methylation Signatures and Classification of Variants in Rare Neurodevelopmental Disorders Using EpigenCentral.

There are more than 700 genes that encode proteins that function in epigenetic regulation and chromatin modification. Germline variants in these genes (typically heterozygous) are associated with rare neurodevelopmental disorders (NDDs) characterized by growth abnormalities and intellectual and developmental delay. Advancements in next-generation sequencing have dramatically increased the detection of pathogenic sequence variants in genes encoding epigenetic machinery associated with NDDs and, concurrently, the number of clinically uninterpretable variants classified as variants of uncertain significance (VUS). Recently, DNA methylation (DNAm) signatures, disorder-specific patterns of DNAm change, have emerged as a functional tool that provides insights into disorder pathophysiology and can classify pathogenicity of variants in NDDs. To date, our group and others have identified DNAm signatures for more than 60 Mendelian neurodevelopmental disorders caused by variants in genes encoding epigenetic machinery. There is broad interest in both the research and clinical communities to develop and catalog DNAm signatures in rare NDDs, but there are challenges in optimizing study design considerations and availability of platforms that integrate bioinformatics tools with the appropriate statistical framework required to analyze genome-wide DNAm data. We previously published EpigenCentral, a platform for analysis of DNAm data in rare NDDs. In this article, we utilize the published Weaver syndrome dataset to provide step-by-step protocols for using EpigenCentral for exploratory analysis to identify DNAm signatures and for classification of NDD variants. We also provide important considerations for experimental design and interpretation of DNAm results. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Exploratory analysis to identify disorder-specific DNAm signatures Basic Protocol 2: Classification of variants associated with neurodevelopmental disorders.

The epigenetic state of EED-Gli3-Gli1 regulatory axis controls embryonic cortical neurogenesis.

SummaryMutations 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.

A PNPLA8 frameshift variant in Australian shepherd dogs with hereditary ataxia.

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.

Phenotypic Overlap in Children with Tall Stature: A Case of Weaver Syndrome

Introduction: Tall stature is defined as length or height more than two standard deviations above the mean for age of the reference population. There are different causes of tall stature from a familial trait or a transient anticipation of growth with no major consequences to growth disorders, such as endocrine disorder and syndromic conditions like overgrowth syndromes. Case Presentation: In this study, we reported the case of a 7-year-old girl with tall stature from birth. The patient showed a generalized overgrowth, associated with extremely advanced bone age, dysmorphic features such as a broad forehead and large extremities, and a slight neurodevelopmental delay. Laboratory tests were normal, and the main hormonal disorders were ruled out. The diagnosis of overgrowth syndrome was suspected according to the clinical presentation, and the diagnosis of Weaver syndrome was confirmed by the finding of the pathogenic mutation c.2050C > T p.(Arg684Cys) in EZH2 gene through next generation sequencing (NGS). Conclusions: Our patient showed phenotypical features related to different overgrowth syndrome characteristics. We underlined the difficulties in reaching a clinical diagnosis in presence of tall stature. The role of molecular biology, particularly genetic analysis by NGS approach, should be considered in cases of tall stature with phenotypic overlap.

Pediatric cervical kyphosis in the MRI era (1984-2008) with long-term follow up: literature review.

Pediatric cervical kyphosis in the MRI era (1984-2008) with long-term follow up: literature review.

Approach to the Patient With Pseudoacromegaly.

Pseudoacromegaly encompasses a heterogeneous group of conditions in which patients have clinical features of acromegaly or gigantism, but no excess of GH or IGF-1. Acromegaloid physical features or accelerated growth in a patient may prompt referral to endocrinologists. Because pseudoacromegaly conditions are rare and heterogeneous, often with overlapping clinical features, the underlying diagnosis may be challenging to establish. As many of these have a genetic origin, such as pachydermoperiostosis, Sotos syndrome, Weaver syndrome, or Cantú syndrome, collaboration is key with clinical geneticists in the diagnosis of these patients. Although rare, awareness of these uncommon conditions and their characteristic features will help their timely recognition.

Posteromedial Hypothalamic Deep Brain Stimulation for Refractory Aggressiveness in a Patient With Weaver Syndrome: Clinical, Technical Report and Operative Video

Deep brain stimulation of the posteromedial hypothalamus (PMH DBS) appears to be an effective treatment for drug-resistant aggressiveness. Weaver syndrome (WS) is a rare genetic disorder in which patients develop some degree of intellectual disability and rarely severe behavioral alterations that may benefit from this procedure. We present the case of a 26-yr-old man diagnosed with WS presenting with uncontrollable self and heteroaggressiveness and disruptive behavior refractory to pharmacological treatment and under severe physical and mechanical restraining measures. The patient was successfully treated with bilateral PMH DBS resulting in affective improvement, greater tolerance for signs of affection, regularization in his sleep pattern and appetite disturbances at 12-mo follow-up. A detailed description and video of the procedure are presented, and a review of the clinical characteristics of WS and the utility and benefits of PMH DBS for refractory aggressiveness are reviewed. To our knowledge, this is the first case of refractory aggressiveness described in WS as well as the first patient with WS successfully treated with PMH DBS.

Commentary: Posteromedial Hypothalamic Deep Brain Stimulation for Refractory Aggressiveness in a Patient With Weaver Syndrome: Clinical, Technical Report and Operative Video.

Commentary: Posteromedial Hypothalamic Deep Brain Stimulation for Refractory Aggressiveness in a Patient With Weaver Syndrome: Clinical, Technical Report and Operative Video.

Advancing clinical dysmorphology diagnostic skills: Weaver syndrome

There are now too many of rare clinical syndromes and dysmorphic syndromes including genetic syndromes, and it is difficult for most physicians to equip themselves with adequate professional knowledge that help them to make an early useful diagnosis for many of the syndromes they may encounter. We have previously described our pioneering extensive experiences with clinical genetics and dysmorphology in a plethora of publications. We have previously reported a large number of rare conditions in Iraq, and we have also helped physicians in the diagnosis and publication of rare syndromes observed in other countries. The aim of this papers is to help clinicians in advancing the diagnostic skills in the field of clinical syndromes by reviewing briefly a rare syndrome that have not been reported in Iraq, but it is associated with certain clinical characteristics that allow clinicians who see the syndrome for the first time, capable of making an easy diagnosis by knowing few information about the condition.

Olfactory Malformations in Mendelian Disorders of the Epigenetic Machinery

Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders called Mendelian Disorders of the Epigenetic Machinery (MDEM). This study aims to determine the prevalence of olfactory malformations in a heterogeneous group of subjects with MDEM. We reviewed the clinical data of 35 patients, 20 females and 15 males, with a mean age of 9.52 years (SD 4.99). All patients had a MDEM and an already available high-resolution brain MRI scan. Two experienced neuroradiologists reviewed the MR images, noting abnormalities and classifying olfactory malformations. Main findings included Corpus Callosum, Cerebellar vermis, and olfactory defects. The latter were found in 11/35 cases (31.4%), of which 7/11 had Rubinstein-Taybi syndrome (RSTS), 2/11 had CHARGE syndrome, 1/11 had Kleefstra syndrome (KLFS), and 1/11 had Weaver syndrome (WVS). The irregularities mainly concerned the olfactory bulbs and were bilateral in 9/11 patients. With over 30% of our sample having an olfactory malformation, this study reveals a possible new diagnostic marker for MDEM and links the epigenetic machinery to the development of the olfactory bulbs.

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

PYROSEQUENCING: ITS POTENTIAL AND LIMITATIONS IN DIAGNOSIS OF INHERITED DISEASES IN CATTLE

A large number of diff erent groups of livestock diseases in which heredity plays a signifi cant role are currently reported. In particular, more than 500 genetically determined morphological and functional disorders have been detected in cattle; for 150 of them, specifi c mutations are known. The sale of bovine genetic materials is associated with the spread of various diseases caused by mutations that occur in the prominent representatives of breeds. The abundance of lethal mutations in the populations requires a broader application of molecular diagnostic methods for detection of monogenic hereditary diseases. DNA pyrosequencing, being the most convenient technique for the rapid diagnosis of single nucleotide mutations in the bovine genome that are located in the regions with known nucleotide sequence, has a potential for meeting this need. Pyrosequencing-based methods for identifi cation of the most common signifi cant mutations in Holstein, Simmental, Brown Swiss and Aberdeen Angus cattle were developed, validated and approved at the FGBU “VGNKI”. Such mutations are associated with leukocyte adhesion defi ciency, complex vertebral malformation, uridine monophosphate synthetase defi ciency, citrullinemia, spinal muscular atrophy, spinal cord demyelination, Brown Swiss haplotype 2, Weaver syndrome, developmental duplications, α-mannosidosis, dwarfi sm, bovine male subfertility, trombocytopathya, arachnomelia syndrome, hypozincemia-like syndrome. These methods are intended to test semen in the breeding centres, scientifi c laboratories working in the fi eld of biotechnology and animal reproduction, livestock reproduction centres. The use of the proposed genetic tests to detect mutant alleles, as well as reduced use of mutation-bearing animals in stock breeding will allow minimizing the occurrence of inherited diseases and thus improving the gene pool of cattle in the country.

Rare SUZ12 variants commonly cause an overgrowth phenotype.

The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.

PRC2-complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes.

The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss-of-function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2-associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED-associated overgrowth (Cohen-Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.

CUL1: Novel Therapeutic Target in Myeloid Neoplasms Harboring -7/Del(7q)

CUL1: Novel Therapeutic Target in Myeloid Neoplasms Harboring -7/Del(7q)