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American Journal of Human Genetics May 2020Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core...
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.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Male; Mosaicism; Mutation; Mutation, Missense; Neoplasm Proteins; Polycomb Repressive Complex 2; Reproducibility of Results; Transcription Factors; Young Adult
PubMed: 32243864
DOI: 10.1016/j.ajhg.2020.03.008 -
Medicine Jan 2018Sugammadex is a cylodextrin derivate that encapsulates steroidal neuromuscular blocker agents and is reported as a safe and well-tolerated drug. In this case report, we... (Review)
Review
Clinically suspected anaphylaxis induced by sugammadex in a patient with Weaver syndrome undergoing restrictive mammoplasty surgery: A case report with the literature review.
RATIONALE
Sugammadex is a cylodextrin derivate that encapsulates steroidal neuromuscular blocker agents and is reported as a safe and well-tolerated drug. In this case report, we present a patient who developed grade 3 anaphylaxis just after sugammadex administration.
PATIENT CONCERNS
A 22-year-old woman with diagnosis of Weaver syndrome was scheduled for bilateral mammoplasty and resection of unilateral accessory breast tissue resection. Anesthesia was induced and maintained by propofol, rocuronium, and remifentanil. At the end of the operation, sugammadex was administered and resulted in initially hypotension and bradycardia then the situation worsened by premature ventricular contraction and bigeminy with tachycardia, bronchospasm, and hypoxia.
DIAGNOSIS
The Ring and Messmer clinical severity scale grade 3 anaphylactic reaction occurred just after sugammadex injection and the patient developed prolonged hypotension with recurrent cardiac arrhythmias in postoperative 12 hours.
INTERVENTIONS
Treatment was initiated bolus injections of ephedrine, epinephrine, lidocaine, steroids and antihistaminic and continued with lidocaine bolus dosages and norepinephrine infusion for the postoperative period.
OUTCOMES
The general condition of the patient improved to normal 3 hours after the sugammadex injection, and she was moved to the intensive care unit. At 2nd and 8th hours of intensive care unit follow-up, she developed premature ventricular contraction and bigeminy with the heart rate of 130 to 135 beats/min, which returned to sinus rhythm with 50 mg lidocaine. After that, no symptoms were observed and the patient was discharged to plastic surgery clinic at the following day.
LESSONS
Sugammadex may result in life-treating anaphylactic reaction even in a patient who did not previously expose to drug. Moreover, prolonged cardiovascular collapse and cardiac arrhythmias may occur.
Topics: Abnormalities, Multiple; Anaphylaxis; Congenital Hypothyroidism; Craniofacial Abnormalities; Female; Hand Deformities, Congenital; Humans; Mammaplasty; Sugammadex; Young Adult; gamma-Cyclodextrins
PubMed: 29505006
DOI: 10.1097/MD.0000000000009661 -
Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome.Journal of Medical Genetics Apr 1998The simultaneous occurrence of familial neurofibromatosis type 1 (NF1) and an overgrowth syndrome resembling Weaver syndrome was observed in two related cases (a mother...
The simultaneous occurrence of familial neurofibromatosis type 1 (NF1) and an overgrowth syndrome resembling Weaver syndrome was observed in two related cases (a mother and her son). NF1 was confirmed by molecular genetic analysis showing a large deletion at 17q11.2, encompassing the entire NF1 gene. The other symptoms in the two cases were similar to the features reported in Weaver syndrome. Although the combination of NF1 and an overgrowth syndrome resembling Weaver syndrome in this family may be fortuitous, we favour the hypothesis that the deletion of the entire gene has caused this combined phenotype. Possible pathogenetic mechanisms are discussed. The observation suggests a relation between NF1 with an extraordinarily large gene deletion and a Weaver(-like) syndrome. This warrants investigation for deletions in the 17q11.2 region in Weaver(-like) syndrome patients.
Topics: Abnormalities, Multiple; Adult; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 17; Female; Genetic Diseases, Inborn; Growth Disorders; Humans; Male; Neurofibromatosis 1; Syndrome
PubMed: 9598729
DOI: 10.1136/jmg.35.4.323 -
Indian Journal of Human Genetics Jan 2009
PubMed: 20407649
DOI: 10.4103/0971-6866.50869 -
Ultrasound in Obstetrics & Gynecology :... Nov 1999To report prospectively the prenatal diagnosis, management and outcome of 14 cases of unilateral ventriculomegaly. (Review)
Review
OBJECTIVE
To report prospectively the prenatal diagnosis, management and outcome of 14 cases of unilateral ventriculomegaly.
METHODS
Fourteen fetuses were diagnosed as having one ventricle of > or = 10 mm, as measured at the level of the atrium.
RESULTS
In ten cases, the scan showed mild unilateral ventriculomegaly with an atrium width between 11 and 13 mm and this remained stable up to term. Eight of these fetuses had a magnetic resonance imaging scan in utero between 32 and 34 weeks of gestation which confirmed the diagnosis of mild ventriculomegaly without other brain abnormalities and showed a normal cortical mantle. No obvious cause was found and the outcome was normal in all cases. In four cases, the unilateral ventriculomegaly evolved rapidly with an atrium width up to 20-25 mm. Causes included atresia of the foramen of Monro, toxoplasmosis, brain atrophy and Weaver syndrome. Three underwent termination of pregnancy and the postmortem examination confirmed the diagnosis. The baby with brain atrophy and schizencephaly had a ventriculoperitoneal shunt placed at 1 month of age and has severe developmental delay at 9 months.
CONCLUSION
The prognosis of unilateral ventriculomegaly is uncertain. Examination of both ventricles during the anomaly scan should be performed, as should ultrasound follow-up of these cases up to the end of the third trimester. Fetuses with an isolated, mild, stable unilateral ventriculomegaly seem to have a favourable neurological outcome. However, fetuses with rapidly evolving unilateral ventriculomegaly or cases associated with other brain abnormalities may have a poor neurological outcome.
Topics: Adult; Female; Gestational Age; Humans; Hydrocephalus; Lateral Ventricles; Male; Pregnancy; Pregnancy Outcome; Prognosis; Prospective Studies; Ultrasonography, Prenatal
PubMed: 10623992
DOI: 10.1046/j.1469-0705.1999.14050327.x -
The Canadian Veterinary Journal = La... Apr 1988A 15-month-old purebred Brown Swiss heifer was presented because of posterior paresis and ataxia. Histopathological examination of the brain and spinal cord showed...
A 15-month-old purebred Brown Swiss heifer was presented because of posterior paresis and ataxia. Histopathological examination of the brain and spinal cord showed evidence of a mild diffuse degenerative myeloencephalopathy. The most severe degenerative lesions were located in the white matter of the thoracic spinal cord. We believe this to be the first documented case of bovine progressive degenerative myeloencephalopathy ("weaver syndrome") in Canada.
PubMed: 17423028
DOI: No ID Found -
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 -
The Journal of Clinical Endocrinology... Apr 2018Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations...
CONTEXT
Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.
OBJECTIVE
To test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function.
DESIGN
Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.
RESULTS
A de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.
CONCLUSION
We generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.
Topics: Abnormalities, Multiple; Animals; Child; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Exome; Hand Deformities, Congenital; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Male; Mice; Mutation
PubMed: 29244146
DOI: 10.1210/jc.2017-01948 -
Genetics, Selection, Evolution : GSE Mar 2016Bovine progressive degenerative myeloencephalopathy (Weaver syndrome) is a neurodegenerative disorder in Brown Swiss cattle that is characterized by progressive hind leg...
BACKGROUND
Bovine progressive degenerative myeloencephalopathy (Weaver syndrome) is a neurodegenerative disorder in Brown Swiss cattle that is characterized by progressive hind leg weakness and ataxia, while sensorium and spinal reflexes remain unaffected. Although the causal mutation has not been identified yet, an indirect genetic test based on six microsatellite markers and consequent exclusion of Weaver carriers from breeding have led to the complete absence of new cases for over two decades. Evaluation of disease status by imputation of 41 diagnostic single nucleotide polymorphisms (SNPs) and a common haplotype published in 2013 identified several suspected carriers in the current breeding population, which suggests a higher frequency of the Weaver allele than anticipated. In order to prevent the reemergence of the disease, this study aimed at mapping the gene that underlies Weaver syndrome and thus at providing the basis for direct genetic testing and monitoring of today's Braunvieh/Brown Swiss herds.
RESULTS
Combined linkage/linkage disequilibrium mapping on Bos taurus chromosome (BTA) 4 based on Illumina Bovine SNP50 genotypes of 43 Weaver-affected, 31 Weaver carrier and 86 Weaver-free animals resulted in a maximum likelihood ratio test statistic value at position 49,812,384 bp. The confidence interval (0.853 Mb) determined by the 2-LOD drop-off method was contained within a 1.72-Mb segment of extended homozygosity. Exploitation of whole-genome sequence data from two official Weaver carriers and 1145 other bulls that were sequenced in Run4 of the 1000 bull genomes project showed that only a non-synonymous SNP (rs800397662) within the PNPLA8 gene at position 49,878,773 bp was concordant with the Weaver carrier status. Targeted SNP genotyping confirmed this SNP as a candidate causal mutation for Weaver syndrome. Genotyping for the candidate causal mutation in a random sample of 2334 current Braunvieh animals suggested a frequency of the Weaver allele of 0.26 %.
CONCLUSIONS
Through combined use of exhaustive sequencing data and SNP genotyping results, we were able to provide evidence that supports the non-synonymous mutation at position 49,878,773 bp as the most likely causal mutation for Weaver syndrome. Further studies are needed to uncover the exact mechanisms that underlie this syndrome.
Topics: Animals; Ataxia; Base Sequence; Breeding; Cattle; Cattle Diseases; Chromosome Mapping; Encephalomyelitis; Genomics; Genotype; Haplotypes; Likelihood Functions; Linkage Disequilibrium; Male; Mutation; Phenotype; Polymorphism, Single Nucleotide
PubMed: 26992691
DOI: 10.1186/s12711-016-0201-5 -
Proceedings of the National Academy of... Apr 2019Enhancer of Zeste Homolog (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and...
Enhancer of Zeste Homolog (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states. Despite their importance, the molecular details of how PRC2 "senses" H3K36 methylation are unclear. We demonstrate that PRC2 is activated in by the unmodified side chain of H3K36, and that this activation results in a fivefold increase in the of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome.
Topics: Binding Sites; Enhancer of Zeste Homolog 2 Protein; Histones; Humans; Models, Molecular; Mutation; Protein Binding; Recombinant Proteins
PubMed: 30967505
DOI: 10.1073/pnas.1819029116