Angelman syndrome: how many genes to remain silent? (original) (raw)
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BMC medical genetics, 2017
Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype. AS is caused by the lack of expression in neurons of the UBE3A gene, which is located in the 15q11.2-q13 imprinted region. Functional loss of UBE3A is due to 15q11.2-q13 deletion, mutations in the UBE3A gene, paternal uniparental disomy and genomic imprinting defects. We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis. Methylation Specific-Multiplex Ligation-Dependent Probe Amplification (MS-MLPA) of the 15q11.2-q13 region was carried out in our laboratory as the first diagnostic tool detecting two novel UBE3A intragenic deletions. Subsequently, the MLPA P336-A2 kit was used to confirm and determine the size of the UBE3A deletion in the two patients. A review of the clinical features of previously reported p...
Molecular Psychiatry
Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11–q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (...
Novel deletion encompassing exons 5–12 of the UBE3A gene in a girl with Angelman syndrome
European Journal of Medical Genetics, 2011
Angelman syndrome (AS) is characterised by severe developmental delay, severe speech impairment, gait ataxia and/or limb tremor and a unique behavioural phenotype. The diagnosis of AS is based on a combination of clinical features and molecular genetic testing. Currently, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies anomalies in about 90% of individuals. The aetiology of the remaining 10% is still unknown.
Mutation Analysis of UBE3A in Angelman Syndrome Patients
The American Journal of Human Genetics, 1998
Angelman syndrome (AS) is caused by chromosome 15q11-q13 deletions of maternal origin, by paternal uniparental disomy (UPD) 15, by imprinting defects, and by mutations in the UBE3A gene. UBE3A encodes a ubiquitin-protein ligase and shows brain-specific imprinting. Here we describe UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. Two identical de novo 5-bp duplications in exon 16 were found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and five were sporadic. In two familial cases and one sporadic case, mosaicism for UBE3A mutations was detected: in the mother of three AS sons, in the maternal grandfather of two AS first cousins, and in the mother of an AS daughter. The frequencies with which we detected mutations were 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases.
The spectrum of mutations in UBE3A causing Angelman syndrome
Human Molecular Genetics, 1999
Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromo-some and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.
New genes involved in Angelman syndrome-like: expanding the genetic spectrum
2020
Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.
Intragenic deletion of UBE3A gene in 2 sisters with Angelman syndrome detected by MLPA
American Journal of Medical Genetics Part A, 2011
Background: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, absent speech, dysmorphic facial features, microcephaly, epileptic seizures, Electroencephalography (EEG) abnormalities and neurological problem. Four known molecular mechanisms lead to a deficiency in maternal UBE3A expression and consequently to AS: (1) Deletion of the AS critical region on the maternal chromosome 15q11.2-q13 (70%), (2) paternal uniparental disomy (pUPD) (2-7%), (3) imprinting defects (3-5%), and (4) mutations in the maternal copy of UBE3A (10%). Materials and methods: Here, we report 11 Tunisian AS patients suspected on the basis of clinical features, behavior, EEG findings and confirmed by molecular analysis using FISH technique, microsatellites study and Methylation Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA). Results: The diagnosis was confirmed in these patients (7 males, 4 females) by detecting the presence of deletion of the critical AS region on chromosome 15 through the use of fluorescence in situ hybridization (FISH) technique in 10 patients, and confirmed by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA). A microsatellite analysis detected only one patient with uniparental disomy. Conclusion: Deletion and methylation aberration screening by MS-MLPA assay is considered as a rapid and cost-effective method to confirm Angelman syndrome diagnosis contributing to an early interventional therapy and genetic counseling should be provided.
Angelman syndrome: advancing the research frontier of neurodevelopmental disorders
Journal of Neurodevelopmental Disorders, 2010
This report is a meeting summary of the 2010 Angelman Syndrome Foundation's scientific symposium on the neuroscience of UBE3A. Angelman syndrome is characterized by loss of speech, severe developmental delay, seizures, and ataxia. These core symptoms are caused by maternal allele disruptions of a single gene—UBE3A. UBE3A encodes an E3 ubiquitin ligase that targets certain proteins for proteasomal degradation. This biology has led to the expectation that the identification of Ube3a protein targets will lead to therapies for Angelman syndrome. The recent discovery of Ube3a substrates such as Arc (activity-regulated cytoskeletal protein) provides new insight into the mechanisms underlying the synaptic function and plasticity deficits caused by the loss of Ube3a. In addition to identifying Ube3a substrates, there have also been recent advances in understanding UBE3A's integrated role in the neuronal repertoire of genes and protein interactions. A developmental picture is now eme...
European Journal of Medical Genetics, 2006
Angelman syndrome (AS) is a neurodevelopmental disorder caused by failure of expression of the maternal copy of the imprinted UBE3A gene through a variety of mechanisms detected by methylation studies, mutation analysis of UBE3A and FISH. In 10-15% of suspected cases of AS these investigations do not reveal a genetic abnormality. We report here the development of a semi-quantitative dosage PCR technique used to identify sub-microscopic deletions involving UBE3A. Using this method we analysed a panel of 26 patients from 24 families, all fulfilling the clinical criteria for AS. We identified a deletion of UBE3A exons 8-16 in a sibling pair. Analysis of parental samples revealed the same deletion in their phenotypically normal mother. This is an inexpensive and valuable method for detecting UBE3A deletions in a small but important proportion of AS cases of unidentifiable cause.