Angelman Syndrome Phenotype Research Articles

Comprehensive molecular and clinical findings in 29 patients with multi-locus imprinting disturbance

BackgroundMulti-locus imprinting disturbance (MLID) with methylation defects in various differentially methylated regions (DMRs) has recently been identified in approximately 150 cases with imprinting disorders (IDs), and deleterious variants have been found in genes related to methylation maintenance of DMRs, such as those encoding proteins constructing the subcortical maternal complex (SCMC), in a small fraction of patients and/or their mothers. However, integrated methylation analysis for DMRs and sequence analysis for MLID-causative genes in MLID cases and their mothers have been performed only in a single study focusing on Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) phenotypes.ResultsOf 783 patients with various IDs we have identified to date, we examined a total of 386 patients with confirmed epimutation and 71 patients with epimutation or uniparental disomy. Consequently, we identified MLID in 29 patients with epimutation confirmed by methylation analysis for multiple ID-associated DMRs using pyrosequencing and/or methylation-specific multiple ligation-dependent probe amplification. MLID was detected in approximately 12% of patients with BWS phenotype and approximately 5% of patients with SRS phenotype, but not in patients with Kagami-Ogata syndrome, Prader-Willi syndrome, or Angelman syndrome phenotypes. We next conducted array-based methylation analysis for 78 DMRs and whole-exome sequencing in the 29 patients, revealing hypomethylation-dominant aberrant methylation patterns in various DMRs of all the patients, eight probably deleterious variants in genes for SCMC in the mothers of patients, and one homozygous deleterious variant in ZNF445 in one patient. These variants did not show gene-specific methylation disturbance patterns. Clinically, neurodevelopmental delay and/or intellectual developmental disorder (ND/IDD) was observed in about half of the MLID patients, with no association with the identified methylation disturbance patterns and genetic variants. Notably, seven patients with BWS phenotype were conceived by assisted reproductive technology (ART).ConclusionsThe frequency of MLID was 7.5% (29/386) in IDs caused by confirmed epimutation. Furthermore, we revealed diverse patterns of hypomethylation-dominant methylation defects, nine deleterious variants, ND/IDD complications in about half of the MLID patients, and a high frequency of MLID in ART-conceived patients.

Prenatal delivery of a therapeutic antisense oligonucleotide achieves broad biodistribution in the brain and ameliorates Angelman syndrome phenotype in mice

Angelman syndrome (AS), an early-onset neurodevelopmental disorder characterized by abnormal gait, intellectual disabilities, and seizures, occurs when the maternal allele of the UBE3A gene is disrupted, since the paternal allele is silenced in neurons by the UBE3A antisense (UBE3A-AS) transcript. Given the importance of early treatment, we hypothesized that prenatal delivery of an antisense oligonucleotide (ASO) would downregulate the murine Ube3a-AS, resulting in increased UBE3A protein and functional rescue. Using a mouse model with a Ube3a-YFP allele that reports on-target ASO activity, we found that in utero, intracranial (IC) injection of the ASO resulted in dose-dependent activation of paternal Ube3a, with broad biodistribution. Accordingly, in utero injection of the ASO in a mouse model of AS also resulted in successful restoration of UBE3A and phenotypic improvements in treated mice on the accelerating rotarod and fear conditioning. Strikingly, even intra-amniotic (IA) injection resulted in systemic biodistribution and high levels of UBE3A reactivation throughout the brain. These findings offer a novel strategy for early treatment of AS using an ASO, with two potential routes of administration in the prenatal window. Beyond AS, successful delivery of a therapeutic ASO into neurons has implications for a clinically feasible prenatal treatment for numerous neurodevelopmental disorders.

Impact of Deletion on Angelman Syndrome Phenotype Variability: Phenotype-Genotype Correlation in 97 Patients with Motor Developmental Delay.

Angelman syndrome (AS) is a rare neurodevelopmental disorder due to genetic defects involving chromosome 15, known by intellectual disability, cognitive and behavioral disorders, ataxia, delayed motor development, and seizures. This study highlights the clinical spectrum and molecular research to establish the genotype-phenotype correlation in the pediatric Moroccan population. Methylation-specific-polymerase chain reaction (MS-PCR) is a primordial technique not only to identify the genetic mechanism of AS but also to characterize the different molecular classes induced in the appearance of the clinical symptoms. Patients with positive methylation profile were additionally studied by fluorescent in situ hybridization. Sequencing analysis of the UBE3A gene was performed for patients with negative MS-PCR. We used Fisher's test to assess differences in the distribution of features frequencies among the deletional and the nondeletional group. Statistical analysis was performed using R project. We identified from 97 patients diagnosed with AS, 14 (2.06%) had a classical AS phenotype, while 70 (84.5%) patients displayed a subset of consistent and frequent criteria. Development delay was shown severe in 63% and moderate in 37%. Nineteen out of 97 of them had MS-PCR positive in which 17 (89.47%) had 15q11-q13 deletion. Deletion patients presented a higher incidence of epileptic seizures ( p = 0.04), ataxia ( p = 0.0008), and abnormal electroencephalogram (EEG) profile ( p = 0.003). We further found out a frameshift deletion located at exon 9 of the UBE3A gene discovered in a 5 years old patient. We report in this study the genotype-phenotype correlation using different molecular testing. Correlation analysis did not reveal any statistical differences in phenotypic dissimilarity between deletion and nondeletion groups for most clinical features, except the correlation was highly significant in the abnormal EEG. According to our findings, we recommend offering MS-PCR analysis to all patients with severe intellectual disability, developmental delay, speech impairment, happy demeanor, and hypopigmentation.

Expanding the clinico-molecular spectrum of Angelman syndrome phenotype with the GABRG3 gene: Evidence from methylation and sequencing studies.

Angelman syndrome (AS) (OMIM#105830) is an imprinting disorder caused due to alterations in the maternal chr 15q11-13 region. Majority of cases can be diagnosed by methylation-specific polymerase chain reaction (MS-PCR) of SNRPN gene and by UBE3A sequencing, however, about 10% of cases with AS phenotype remain undiagnosed. Differential diagnoses of AS can be detected by chromosomal microarray (CMA) and clinical exome sequencing (CES). In this study, 30 cases with AS features were evaluated by MS-PCR, CMA, and CES. SNRPN MS-PCR confirmed AS in eight (26%), CMA and CES diagnosed nine (30%) cases. One case was identified with a novel variant c.1125C>T in GABRG3, located at 15q12 region, which is currently not associated with any syndrome. The GABRG3 gene is also speculated to be imprinted, a MS-PCR assay was designed to confirm its differential parental methylation status. This assay identified another case with altered GABRG3 methylation. The two cases with GABRG3 alteration-sequence change and methylation indicate that GABRG3 may be associated with a subtype of AS or a new related syndrome. Performing GABRG3 MS-PCR and sequencing of a larger group of patients with AS phenotype and normal SNPRN and UBE3A status will help in establishing exact genotype-phenotype correlation.

CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice.

Gene editing holds the potential to correct mutations and cure devastating genetic disorders. The technology has not yet proven efficacious for therapeutic use in CNS diseases with ubiquitous neuronal defects. Angelman syndrome (AS), a severe neurodevelopmental disorder, is caused by a lack of maternal expression of the UBE3A gene. Because of genomic imprinting, only neurons are affected. One therapeutic approach focuses on the intact paternal UBE3A copy in patients with AS that is silenced by an antisense transcript (UBE3A-ATS). We show here that gene editing of Ube3a-ATS in the mouse brain resulted in the formation of base pair insertions/deletions (indels) in neurons and the subsequent unsilencing of the paternal Ube3a allele in neurons, which partially corrected the behavioral phenotype of a murine AS model. This study provides compelling evidence to further investigate editing of the homologous region of the human UBE3A-ATS because this may provide a lasting therapeutic effect for patients with AS.

Refining the Behavioral Phenotype of Angelman Syndrome: Examining Differences in Motivation for Social Contact Between Genetic Subgroups.

Angelman syndrome (AS) is caused by loss of information from the 15q11.2-13 region on the maternal chromosome with striking phenotypic difference from Prader–Willi syndrome in which information is lost from the same region on the paternal chromosome. Motivation for social contact and sensory seeking behaviors are often noted as characteristics of the phenotype of AS and it has been argued that the strong drive for social contact supports a kinship theory interpretation of genomic imprinting. In this study we developed an experimental paradigm for quantifying the motivation for social contact in AS and examined differences across the genetic subtypes that cause AS [deletion, imprinting centre defect (ICD), uniparental disomy and UBE3A mutation]. Using single case experimental designs we examined the rate of acquisition of behavioral responses using operant learning paradigms for 21 children with AS whilst systematically varying the nature of social and sensory reinforcement. Variability in rates of acquisition was influenced by the nature of rewarding stimuli. Across the total sample both sensory stimuli and social contact could increase the rate of rewarded behavior with difference between children in the most effective reward. A striking difference in the rewarding properties of social contact across genetic subtypes was evidenced by non-deletion genetic causes of AS showing significantly higher rates of responding than the deletion cause in the social reinforcement paradigm. The results indicate that reinforcer assessment can beneficially inform behavioral interventions and that within syndrome variability in the behavioral phenotype of AS is likely driven by genetic difference. The non-deletion cause of AS, and particularly the ICD group, may be the optimal group for further study of genomic imprinting.

Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes

BackgroundAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of Ube3a gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development.FindingsUsing a conditional mouse, we deleted the Ube3a gene at three ages spanning brain maturation. We assessed the consequences of Ube3a gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of Ube3a recapitulated all behavioral deficits of AS mice. In contrast, Ube3a gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity.ConclusionsTaken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit.

Genetic variation of UBE3A is associated with schizotypy in a population of typical individuals

The maternally expressed imprinted gene UBE3A has been implicated in autism, schizophrenia and psychosis. The phenotype of Angelman syndrome, caused by loss of UBE3A expression, involves autism spectrum traits, while Prader-Willi syndrome, where the genotype of maternal disomy increases dosage of UBE3A, shows high penetrance for the development of psychosis. Maternal duplications of the 15q11-q13 chromosome region that overlap the imprinted region also show an association with schizophrenia, further implying a connection between increased dosage of UBE3A and the development of schizophrenia and psychosis. We phenotyped a large population of typical individuals for autism spectrum and schizotypal traits and genotyped them for a set of SNPs in UBE3A. Genetic variation of rs732739, an intronic SNP tagging a large haplotype spanning nearly the entire range of UBE3A, was significantly associated with variation in total schizotypy. Our results provide an independent line of evidence, connecting the imprinted UBE3A gene to the schizophrenia spectrum.

Strain-dependence of the Angelman Syndrome phenotypes in Ube3a maternal deficiency mice

Angelman syndrome (AS) is a genetic neurodevelopmental disorder, most commonly caused by deletion or mutation of the maternal allele of the UBE3A gene, with behavioral phenotypes and seizures as key features. Currently no treatment is available, and therapeutics are often ineffective in controlling AS-associated seizures. Previous publications using the Ube3a maternal deletion model have shown behavioral and seizure susceptibility phenotypes, however findings have been variable and merit characterization of electroencephalographic (EEG) activity. In this study, we extend previous studies comparing the effect of genetic background on the AS phenotype by investigating the behavioral profile, EEG activity, and seizure threshold. AS C57BL/6J mice displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. AS 129 mice performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. AS F1 hybrid mice (C57BL/6J × 129) showed milder behavioral impairments, infrequent EEG polyspikes, and fewer spectral power alterations. These findings indicate the effect of common genetic backgrounds on the Ube3a maternal deletion behavioral, EEG, and seizure threshold phenotypes. Our results will inform future studies on the optimal strain for evaluating therapeutics with different AS-like phenotypes.

From Cortical and Subcortical Grey Matter Abnormalities to Neurobehavioral Phenotype of Angelman Syndrome: A Voxel-Based Morphometry Study.

Angelman syndrome (AS) is a rare neurogenetic disorder due to loss of expression of maternal ubiquitin-protein ligase E3A (UBE3A) gene. It is characterized by severe developmental delay, speech impairment, movement or balance disorder and typical behavioral uniqueness. Affected individuals show normal magnetic resonance imaging (MRI) findings, although mild dysmyelination may be observed. In this study, we adopted a quantitative MRI analysis with voxel-based morphometry (FSL-VBM) method to investigate disease-related changes in the cortical/subcortical grey matter (GM) structures. Since 2006 to 2013 twenty-six AS patients were assessed by our multidisciplinary team. From those, sixteen AS children with confirmed maternal 15q11-q13 deletions (mean age 7.7 ± 3.6 years) and twenty-one age-matched controls were recruited. The developmental delay and motor dysfunction were assessed using Bayley III and Gross Motor Function Measure (GMFM). Principal component analysis (PCA) was applied to the clinical and neuropsychological datasets. High-resolution T1-weighted images were acquired and FSL-VBM approach was applied to investigate differences in the local GM volume and to correlate clinical and neuropsychological changes in the regional distribution of GM. We found bilateral GM volume loss in AS compared to control children in the striatum, limbic structures, insular and orbitofrontal cortices. Voxel-wise correlation analysis with the principal components of the PCA output revealed a strong relationship with GM volume in the superior parietal lobule and precuneus on the left hemisphere. The anatomical distribution of cortical/subcortical GM changes plausibly related to several clinical features of the disease and may provide an important morphological underpinning for clinical and neurobehavioral symptoms in children with AS.

Paternally Inherited GABRB3 Intragenic Deletion in a Boy with Autistic Features and Angelman Syndrome Phenotype–Case Report and Literature Review

We report on a 4 year old patient with a unique paternally inherited single-exon GABRB3 gene deletion and clinical findings of severe speech delay, intellectual disability, autistic features, unusual behavior, tremor, and history of seizures and gait abnormalities. Similarities and significant differences with other cases involving rearrangements of 15q11-q13 are discussed. Further on, we provide literature review of the clinical picture of GABRB3 mutations.

The neurobehavioral and molecular phenotype of Angelman Syndrome.

Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain-derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research.

Disruption of the LTD dialogue between the cerebellum and the cortex in Angelman syndrome model: a timing hypothesis.

Angelman syndrome (AS) is a genetic neurodevelopmental disorder in which cerebellar functioning impairment has been documented despite the absence of gross structural abnormalities. Characteristically, a spontaneous 160 Hz oscillation emerges in the Purkinje cells network of the Ube3am−/p+ Angelman mouse model. This abnormal oscillation is induced by enhanced Purkinje cell rhythmicity and hypersynchrony along the parallel fiber beam. We present a pathophysiological hypothesis for the neurophysiology underlying major aspects of the clinical phenotype of AS, including cognitive, language and motor deficits, involving long-range connection between the cerebellar and the cortical networks. This hypothesis states that the alteration of the cerebellar rhythmic activity impinges cerebellar long-term depression (LTD) plasticity, which in turn alters the LTD plasticity in the cerebral cortex. This hypothesis was based on preliminary experiments using electrical stimulation of the whiskers pad performed in alert mice showing that after a 8 Hz LTD-inducing protocol, the cerebellar LTD accompanied by a delayed response in the wild type (WT) mice is missing in Ube3am−/p+ mice and that the LTD induced in the barrel cortex following the same peripheral stimulation in wild mice is reversed into a LTP in the Ube3am−/p+ mice. The control exerted by the cerebellum on the excitation vs. inhibition balance in the cerebral cortex and possible role played by the timing plasticity of the Purkinje cell LTD on the spike–timing dependent plasticity (STDP) of the pyramidal neurons are discussed in the context of the present hypothesis.

Molecular and cytogenetic analyses of a patient with Prader-Willi syndrome who also had the phenotype of Angelman syndrome

Most cases of Prader-Willi syndrome are caused by partial deletion of the paternally derived chromosome 15, while maternally derived chromosome 15 is responsible for Angelman syndrome. We report the results of molecular and cytogenetic analyses of a patient who was given a final diagnosis of Prader-Willi syndrome, but also had manifestations consistent with Angelman syndrome. The patient was a 15-year-old boy. After birth, PraderWilli syndrome was diagnosedon fluorescence in situ hybridization (FISH), performed because of muscular hypotonia, failure to thrive, and bilateral cryptorchidism. However, at the age of 2 years, the diagnosis was revised to Angelman syndrome because of atypical absence, characteristic electroencephalographic discharges, mental retardation, and excessive laughter. At the age of 14 years, type 2 diabetes developed, and he is now receivinginsulin glargine and voglibose. The height is 147.0 cm (-3.68 SD), and the body weight is 55.0 kg (body mass index, 25.5 kg/m 2 ). He cannot speak any meaningful words or walk. He has hyperphagia, hypopigmentation, almond-shaped eyes, small hands and feet, and a large mouth and jaw. Chromosomal examination by G-banding stain revealed that the karyotype was a mosaic composed of 45, XY, der(1) t(1;15)(p36.3; q13), -15 and 46, XY, der(1) t(1;15) (p36.3; q13),-15 ,+mar. FISH did not detect signals of UBE3A/D15S10 with the probe for Angelman syndrome or SNRPN for Prader-Willi syndrome on the der(1) chromosome. The marker chromosome was derived from the short arm of chromosome 15. Methylation-specific PCR amplified the SNRPN gene using only primers specific for methylated gene. FISH for 1p36 deletion syndrome did not detect the deletion on the der(1) chromosome. We concluded that his diagnosis was Prader-Willi syndrome caused by the partial deletion of the long arm of chromosome 15, which had translocated onto chromosome 1. The clinical manifestations might have beenmodified by the complicatedstructural changes in chromosomesas well as by possible terminal deletion of the short arm of chromosome 1, which could not be detected on FISH.

Incontinence in individuals with Angelman syndrome: A comparative study

Frequency and type of incontinence and variables associated with incontinence were assessed in individuals with Angelman syndrome (AS; n=71) and in a matched control group (n=69) consisting of individuals with non-specific intellectual disability (ID). A Dutch version of the "Parental Questionnaire: Enuresis/Urinary Incontinence" (Beetz, von Gontard, & Lettgen, 1994) was administered and information on primary caretakers' perspectives regarding each individual's incontinence was gathered. Results show that diurnal incontinence and fecal incontinence during the day more frequently occurred in the control group than in the AS group. In both groups, nocturnal enuresis was the most common form of incontinence. More incontinence was seen in individuals with AS who were younger, had a lower level of adaptive functioning and/or had epilepsy. Individuals with AS were able to stay dry for longer periods of time than the controls and often showed both in-toilet urination and urinary accidents during the day, whereas accidents and correct voids during the day were more set apart in the control group. Also, persons with AS had a lower micturition frequency implying possible voiding postponement. Both groups showed high rates of LUTS (lower urinary tract symptoms) possibly indicative of functional bladder disorders such as voiding postponement, dysfunctional voiding, or even an underactive bladder. In general, most primary caretakers reported severe intellectual disability as the main cause for urinary incontinence. Based on these results incontinence does not appear to be part of the behavioral phenotype of Angelman syndrome. Therefore, pediatric or urologic diagnostics and treatment are recommended for all persons with incontinence and intellectual disability. Further implications for practice and research are given.

Toilet training in individuals with Angelman syndrome: A case series

Objective: To assess if adapted versions of the response restriction toilet training protocol, based on the behavioral phenotype of Angelman syndrome (AS), were successful in fostering urinary continence in seven individuals with AS.Method: Data were collected in AB-designs during baseline, training, generalization and follow-up. The response restriction protocol was adapted: individuals were trained in their natural environment, were prompted to void and along with improving continence, the interval between voids was prolonged and time-on-toilet decreased.Results: During generalization five individuals had less than two accidents and one to six correct voids per day; during baseline more accidents and/or less correct voids occurred. In two participants correct voids increased, but several accidents still occurred. Three participants maintained positive results after 3–18 months.Conclusion: Despite their intellectual and behavioral challenges, urinary continence can be acquired in AS. Several indications of voiding dysfunctions were found; further research is indicated.

Algorithmic Approach for Methyl-CpG Binding Protein 2 (MECP2) Gene Testing in Patients With Neurodevelopmental Disabilities

Methyl-CpG binding protein 2 gene (MECP2) testing is indicated for patients with numerous clinical presentations, including Rett syndrome (classic and atypical), unexplained neonatal encephalopathy, Angelman syndrome, nonspecific mental retardation, autism (females), and an X-linked family history of developmental delay. Because of this complexity, a gender-specific approach for comprehensive MECP2 gene testing is described. Briefly, sequencing of exons 1 to 4 of MECP2 is recommended for patients with a Rett syndrome phenotype, unexplained neonatal encephalopathy, an Angelman syndrome phenotype (with negative 15q11-13 analysis), nonspecific mental retardation, or autism (females). Additional testing for large-scale MECP2 deletions is recommended for patients with Rett syndrome or Angelman syndrome phenotypes (with negative 15q11-13 analysis) following negative sequencing. Alternatively, testing for large-scale MECP2 duplications is recommended for males presenting with mental retardation, an X-linked family history of developmental delay, and a significant proportion of previously described clinical features (particularly a history of recurrent respiratory infections).

Two distinctive classic genetic syndromes, 22q11.2 deletion syndrome and Angelman syndrome, occurring within the same family

We document a sib pair born to a mother with a reciprocal translocation, t(15;22)(q13;q11.2): the daughter had the Angelman syndrome phenotype associated with a maternally derived 15q deletion, and the son had a phenotype associated with a 22q deletion. Adjacent two-type segregation during gametogenesis in the mother can account for the unbalanced karyotypes of the siblings. From a tetravalent chromatid formed by normal chromosome 15, derivative chromosome 15, normal chromosome 22, and derivative chromosome 22, the daughter inherited chromosome 22 and derivative chromosome 22 and the son inherited chromosome 15 and derivative chromosome 15. The family is unique in that two distinctive genetic syndromes, 22q11.2 deletion syndrome and Angelman syndrome, occurred within the same family. The family is also elucidative from an educational standpoint in that major concepts of non-Mendelian inheritance (microdeletion, genomic imprinting, and reciprocal translocation) need to be considered to appreciate the inheritance pattern. Furthermore, the family illustrates the importance of cryptic rearrangements at the most proximal end of acrocentric chromosomes in the evaluation of siblings with multiple congenital anomaly-mental retardation phenotypes that are dissimilar among affected siblings. The situation is analogous to parental balanced translocation between the most "distal" segments of a chromosome, that is, the subtelomere region, a recently appreciated cause of familial recurrence of multiple congenital anomaly-mental retardation phenotype with a normal G-banding karyotype. We suggest that cryptic rearrangements at the most proximal end, analogous to those at the most distal end, should be considered as an appreciable cause of recurrent multiple congenital anomaly-mental retardation phenotype.

Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1–4 genes and practical aspects

Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1–4 genes and practical aspects

Angelman Syndrome Due to a Novel Splicing Mutation of theUBE3AGene

Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, absence of speech, seizures, abnormal electroencephalography (EEG), and happy disposition. The syndrome results from lack of function of the maternal copy of the UBE3A gene on the imprinted Prader-Willi/Angelman syndrome critical region; it is caused by large deletions, paternal uniparental disomy, imprinting center defects or UBE3A deletions, and point mutations. We found a novel splice-site mutation of the UBE3A gene in a child with clinical and EEG features of Angelman syndrome. This case further points out the fact that individuals with Angelman syndrome and mutations of the UBE3A gene have a phenotype that tends to be rather mild, however, undistinguishable, both from the clinical and the electrophysiological points of view, from the Angelman syndrome phenotype due to other known molecular mechanisms.