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American Journal of Medical Genetics.... Feb 2017Weaver syndrome is a rare condition characterized by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic...
Weaver syndrome is a rare condition characterized by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features. Pathogenic variants in EZH2, a histone methyltransferase, have previously been identified as a cause of Weaver syndrome. However, the underlying molecular cause in many patients remains unknown. We report a patient with a clinical diagnosis of Weaver syndrome whose exome was initially non-diagnostic. Reports in the medical literature of EED associated overgrowth prompted re-analysis of the patient's original exome data. The patient was found to have a likely pathogenic variant in EED. These findings support that Weaver syndrome is a disorder with locus heterogeneity and can be due to pathogenic variants in either EZH2 or EED. This case highlights the utility of exome sequencing as a clinical diagnostic tool for novel gene discovery as well as the importance of re-examination of exome data as new information about gene-disease associations becomes available. © 2016 Wiley Periodicals, Inc.
Topics: Abnormalities, Multiple; Comparative Genomic Hybridization; Congenital Hypothyroidism; Craniofacial Abnormalities; Facies; Female; Genetic Association Studies; Hand Deformities, Congenital; Humans; Infant; Mutation; Phenotype; Physical Examination; Polycomb Repressive Complex 2; Sequence Analysis, DNA
PubMed: 27868325
DOI: 10.1002/ajmg.a.38055 -
American Journal of Medical Genetics Oct 1998Weaver syndrome (WS), a condition first described in 1974 by Weaver et al., consists of macrosomia, advanced skeletal age, characteristic pattern of facial and...
Weaver syndrome (WS), a condition first described in 1974 by Weaver et al., consists of macrosomia, advanced skeletal age, characteristic pattern of facial and radiographic anomalies, and contractures. Although there have been three reports of close relatives (sibs or both parent and offspring) affected with this condition, the syndrome generally occurs sporadically, and the recurrence risk in sporadic cases appears to be low. We report here on a family in which the propositus and his sister were born with the facial phenotype, club feet, and macrosomia characteristic of WS. Their father had macrosomia and macrocephaly as an adult, and childhood photos show clearly that he has WS. Two sisters of the propositus have had normal growth and development. The syndrome in this family appears to be inherited in an autosomal dominant fashion.
Topics: Craniofacial Abnormalities; Female; Fetal Macrosomia; Foot Deformities, Congenital; Genes, Dominant; Growth Disorders; Humans; Infant, Newborn; Male; Syndrome
PubMed: 9781912
DOI: 10.1002/(sici)1096-8628(19981002)79:4<305::aid-ajmg13>3.0.co;2-v -
Development (Cambridge, England) Oct 2019Polycomb repressive complex 2 (PRC2) is a conserved chromatin regulator that is responsible for the methylation of histone H3 lysine 27 (H3K27). PRC2 is essential for... (Review)
Review
Polycomb repressive complex 2 (PRC2) is a conserved chromatin regulator that is responsible for the methylation of histone H3 lysine 27 (H3K27). PRC2 is essential for normal development and its loss of function thus results in a range of developmental phenotypes. Here, we review the latest advances in our understanding of mammalian PRC2 activity and present an updated summary of the phenotypes associated with its loss of function in mice. We then discuss recent studies that have highlighted regulatory interplay between the modifications laid down by PRC2 and other chromatin modifiers, including NSD1 and DNMT3A. Finally, we propose a model in which the dysregulation of these modifications at intergenic regions is a shared molecular feature of genetically distinct but highly phenotypically similar overgrowth syndromes in humans.
Topics: Animals; Congenital Abnormalities; Embryonic Development; Humans; Mammals; Models, Biological; Polycomb Repressive Complex 2; Signal Transduction
PubMed: 31575610
DOI: 10.1242/dev.181354 -
European Journal of Pediatrics Nov 1981A boy with primordial overgrowth, macrocephaly, and anomalies of the face, nails, feet and skeleton is reported. Two cases in the literature- referred to as Weaver...
A boy with primordial overgrowth, macrocephaly, and anomalies of the face, nails, feet and skeleton is reported. Two cases in the literature- referred to as Weaver syndrome- exhibited nearly identical anomalies. All three cases were sporadic. Main symptoms of the Weaver syndrome are increased birth weight, early overgrowth, macrocephaly, accelerated osseous maturation, typical facies, hoarse, low pitched voice, hypertonia of muscles and mild developmental delay. Further symptoms are thin, deep-set nails, talipes equinovarus, widened distal femora, and some minor abnormalities. A second boy with primordial overgrowth and macrocephaly demonstrated some, but not all, the symptoms of this syndrome. Whether this boy showed a milder expression of the Weaver syndrome or benign familial macrocephaly is discussed.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Face; Growth Disorders; Humans; Infant; Male; Muscle Hypertonia; Skull; Syndrome
PubMed: 7318839
DOI: 10.1007/BF00443257 -
The Journal of Pediatrics Apr 1983
Topics: Adult; Age Determination by Skeleton; Bone Development; Bone Diseases, Developmental; Carpal Bones; Facial Expression; Female; Femur; Fingers; Heart Septal Defects, Atrial; Humans; Infant, Newborn; Intellectual Disability; Male; Syndrome
PubMed: 6834195
DOI: 10.1016/s0022-3476(83)80195-4 -
Clinical Genetics Sep 1985A boy and his mother had dysmorphic features and accelerated growth of prenatal onset suggestive of the Weaver syndrome. Both had endocrinologic abnormalities. The boy...
A boy and his mother had dysmorphic features and accelerated growth of prenatal onset suggestive of the Weaver syndrome. Both had endocrinologic abnormalities. The boy had very low, hGH, which did not respond to stimulation. The mother had low, non-stimulate hGH hyperprolactinemia with secondary amenorrhea and galactorrhea. This is the first report of a mother to son transmission of the condition.
Topics: Abnormalities, Multiple; Adult; Child; Endocrine System Diseases; Female; Gigantism; Growth Hormone; Humans; Hyperprolactinemia; Male; Syndrome
PubMed: 4064364
DOI: 10.1111/j.1399-0004.1985.tb00396.x -
Indian Journal of Human Genetics May 2007We describe a girl with Sotos syndrome presenting at two and a half years age with developmental delay. She has camptodactyly which has not previously been reported in...
We describe a girl with Sotos syndrome presenting at two and a half years age with developmental delay. She has camptodactyly which has not previously been reported in Sotos syndrome but is a common finding in Weaver syndrome. Both these conditions have been reported to have NSD1 gene mutations. This report is consistent with the conditions being allelic.
PubMed: 21957350
DOI: 10.4103/0971-6866.34711 -
American Journal of Medical Genetics.... Apr 2019Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an...
Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.
Topics: Abnormalities, Multiple; Adult; Child; Congenital Hypothyroidism; Craniofacial Abnormalities; Developmental Disabilities; Enhancer of Zeste Homolog 2 Protein; Female; Fingers; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Microcephaly; Muscle Hypotonia; Mutation; Myopia; Obesity; Phenotype; Polycomb Repressive Complex 2; Retinal Degeneration; Exome Sequencing; Young Adult
PubMed: 30793471
DOI: 10.1002/ajmg.a.61066 -
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 -
Paediatric Anaesthesia Oct 2005Weaver syndrome is a rare disorder of unknown etiology characterized by skeletal overgrowth, distinctive craniofacial and digital abnormalities, and advanced bone age....
Weaver syndrome is a rare disorder of unknown etiology characterized by skeletal overgrowth, distinctive craniofacial and digital abnormalities, and advanced bone age. The prime anesthetic problem reported in children with Weaver syndrome is difficulty with tracheal intubation, resulting in part from relative micrognathia, short neck, and an anterior and cephalad position of the larynx. In this report, the authors describe their experience with two children diagnosed with Weaver syndrome who presented for dental surgery. Contrary to previous reports, tracheal intubation was accomplished with relative ease, suggesting that difficulty in intubation in Weaver syndrome may be age-related, diminishing with advancing age and growth of the mandible, as has been reported for other micrognathic syndromes such as Pierre Robin sequence.
Topics: Anesthesia, General; Anesthetics, Inhalation; Child; Child, Preschool; Dental Restoration, Permanent; Humans; Intubation, Intratracheal; Isoflurane; Male; Micrognathism
PubMed: 16176320
DOI: 10.1111/j.1460-9592.2004.01545.x