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Saudi Journal of Anaesthesia 2016Weaver syndrome is a rare disorder of unknown etiology characterized by skeletal overgrowth, distinctive craniofacial and digital abnormalities and advanced bone age. In...
Weaver syndrome is a rare disorder of unknown etiology characterized by skeletal overgrowth, distinctive craniofacial and digital abnormalities and advanced bone age. In general, craniofacial abnormalities that cause difficulty with tracheal intubation may improve, worsen, or remain unchanged as craniofacial structures mature. Furthermore, there is an estimated risk in these children of ≤1.09% of rhabdomyolysis or malignant hyperpyrexia. We report a case of a boy with Weaver syndrome who underwent emergency evacuation of extra-dural hematoma under general anesthesia.
PubMed: 26955318
DOI: 10.4103/1658-354X.169485 -
Human Mutation Mar 2016Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual...
Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.
Topics: Abnormalities, Multiple; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Infant; Infant, Newborn; Male; Polycomb Repressive Complex 2
PubMed: 26694085
DOI: 10.1002/humu.22946 -
Nature Communications Dec 2015Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by...
Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
Topics: DNA Methylation; Gene Expression Regulation; Genome, Human; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Nuclear Proteins; Sotos Syndrome
PubMed: 26690673
DOI: 10.1038/ncomms10207 -
American Journal of Medical Genetics.... Dec 2013Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the...
Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.
Topics: Abnormalities, Multiple; Adolescent; Child; Child, Preschool; Chromosome Deletion; Congenital Hypothyroidism; Craniofacial Abnormalities; Developmental Disabilities; Enhancer of Zeste Homolog 2 Protein; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Mutation; Phenotype; Polycomb Repressive Complex 2; Sotos Syndrome
PubMed: 24214728
DOI: 10.1002/ajmg.a.36229 -
American Journal of Medical Genetics.... May 2013NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin...
NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2 is a major proto-oncogene and mono- and biallelic activating and inactivating somatic mutations occur as early events in the development of tumors, particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains. EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Many additional questions about the molecular and clinical features of NSD1 and EZH2 remain unanswered. However, studies are underway to address these and, as more cases are ascertained and technology improves, it is hoped that these will, in time, be answered.
Topics: Enhancer of Zeste Homolog 2 Protein; Germ-Line Mutation; Growth; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Polycomb Repressive Complex 2; Proto-Oncogene Mas; Proto-Oncogenes
PubMed: 23592277
DOI: 10.1002/ajmg.c.31359 -
PloS One 2013Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) is a recessive neurological disease that has been observed in the Brown Swiss cattle breed since...
Bovine Progressive Degenerative Myeloencephalopathy (Weaver Syndrome) is a recessive neurological disease that has been observed in the Brown Swiss cattle breed since the 1970's in North America and Europe. Bilateral hind leg weakness and ataxia appear in afflicted animals at 6 to 18 months of age, and slowly progresses to total loss of hind limb control by 3 to 4 years of age. While Weaver has previously been mapped to Bos taurus autosome (BTA) 4∶46-56 Mb and a diagnostic test based on the 6 microsatellite (MS) markers is commercially available, neither the causative gene nor mutation has been identified; therefore misdiagnosis can occur due to recombination between the diagnostic MS markers and the causative mutation. Analysis of 34,980 BTA 4 SNPs genotypes derived from the Illumina BovineHD assay for 20 Brown Swiss Weaver carriers and 49 homozygous normal bulls refined the Weaver locus to 48-53 Mb. Genotyping of 153 SNPs, identified from whole genome sequencing of 10 normal and 10 carrier animals, across a validation set of 841 animals resulted in the identification of 41 diagnostic SNPs that were concordant with the disease. Except for one intergenic SNP all are associated with genes expressed in nervous tissues: 37 distal to NRCAM, one non-synonymous (serine to asparagine) in PNPLA8, one synonymous and one non-synonymous (lysine to glutamic acid) in CTTNBP2. Haplotype and imputation analyses of 7,458 Brown Swiss animals with Illumina BovineSNP50 data and the 41 diagnostic SNPs resulted in the identification of only one haplotype concordant with the Weaver phenotype. Use of this haplotype and the diagnostic SNPs more accurately identifies Weaver carriers in both Brown Swiss purebred and influenced herds.
Topics: Amyotrophic Lateral Sclerosis; Animals; Base Sequence; Cattle; Cattle Diseases; Cell Adhesion Molecules; Central Nervous System Diseases; Chromosome Mapping; Genes, Recessive; Genome-Wide Association Study; Genotype; Haplotypes; Humans; Lipase; Molecular Sequence Data; Myelin Sheath; Nerve Tissue Proteins; Neurodegenerative Diseases; Phenotype; Polymorphism, Single Nucleotide; Sequence Alignment; Sequence Analysis, DNA; Species Specificity
PubMed: 23527149
DOI: 10.1371/journal.pone.0059251 -
Oncotarget Jan 2012Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1. This gene also encodes a histone methyltransferase, in...
Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1. This gene also encodes a histone methyltransferase, in this case with activity against histone H3 lysine 36. NSD1 is mutated in carcinoma of the upper aerodigestive tract (www.sanger.ac.uk/genetics/CGP/cosmic/) and also fuses to NUP98 in acute myeloid leukemia. Looking more widely, whole exome screens in lymphoma, multiple myeloma, renal carcinoma and other malignancies have identified genes encoding diverse histone modifiers as targets of somatic mutation. Strikingly, several of these (e.g. MLL2, EP300, CREBBP, ASXL1) are also mutated in human developmental disorders thus pointing towards a remarkable and unexpected convergence between somatic and germline genetics.
Topics: Abnormalities, Multiple; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA-Binding Proteins; Female; Germ-Line Mutation; Hand Deformities, Congenital; Humans; Male; Transcription Factors
PubMed: 22287508
DOI: 10.18632/oncotarget.436 -
Oncotarget Dec 2011The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a...
The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.
Topics: Abnormalities, Multiple; Amino Acid Sequence; Body Height; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Facies; Female; Germ-Line Mutation; Growth Disorders; Hand Deformities, Congenital; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Male; Polycomb Repressive Complex 2; Sequence Analysis, DNA; Transcription Factors
PubMed: 22190405
DOI: 10.18632/oncotarget.385 -
American Journal of Human Genetics Jan 2012We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare...
We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.
Topics: Abnormalities, Multiple; Adolescent; Adult; Base Sequence; Child; Child, Preschool; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Mutational Analysis; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Exome; Female; Hand Deformities, Congenital; Humans; Infant; Male; Molecular Sequence Data; Mutation; Pedigree; Polycomb Repressive Complex 2; Transcription Factors; Young Adult
PubMed: 22177091
DOI: 10.1016/j.ajhg.2011.11.018 -
PloS One Apr 2011Tyrolean Grey cattle represent a local breed with a population size of ∼5000 registered cows. In 2003, a previously unknown neurological disorder was recognized in...
Tyrolean Grey cattle represent a local breed with a population size of ∼5000 registered cows. In 2003, a previously unknown neurological disorder was recognized in Tyrolean Grey cattle. The clinical signs of the disorder are similar to those of bovine progressive degenerative myeloencephalopathy (weaver syndrome) in Brown Swiss cattle but occur much earlier in life. The neuropathological investigation of an affected calf showed axonal degeneration in the central nervous system (CNS) and femoral nerve. The pedigrees of the affected calves suggested a monogenic autosomal recessive inheritance. We localized the responsible mutation to a 1.9 Mb interval on chromosome 16 by genome-wide association and haplotype mapping. The MFN2 gene located in this interval encodes mitofusin 2, a mitochondrial membrane protein. A heritable human axonal neuropathy, Charcot-Marie-Tooth disease-2A2 (CMT2A2), is caused by MFN2 mutations. Therefore, we considered MFN2 a positional and functional candidate gene and performed mutation analysis in affected and control Tyrolean Grey cattle. We did not find any non-synonymous variants. However, we identified a perfectly associated silent SNP in the coding region of exon 20 of the MFN2 gene. This SNP is located within a putative exonic splice enhancer (ESE) and the variant allele leads to partial retention of the entire intron 19 and a premature stop codon in the aberrant MFN2 transcript. Thus we have identified a highly unusual splicing defect, where an exonic single base exchange leads to the retention of the preceding intron. This splicing defect represents a potential explanation for the observed degenerative axonopathy. Marker assisted selection can now be used to eliminate degenerative axonopathy from Tyrolean Grey cattle.
Topics: Animals; Axons; Cattle; Cattle Diseases; Chromosome Mapping; DNA Mutational Analysis; Gene Expression Regulation; Genetic Predisposition to Disease; Genome-Wide Association Study; Homozygote; Humans; Inheritance Patterns; Mitochondria; Mitochondrial Proteins; Molecular Sequence Data; Muscle Fibers, Skeletal; Mutation; Nerve Degeneration; Phenotype; RNA Splice Sites; RNA, Messenger
PubMed: 21526202
DOI: 10.1371/journal.pone.0018931