Paternal Uniparental Disomy Of Chromosome Research Articles

Beckwith–Wiedemann syndrome with juvenile fibrous nodules and lobular breast tumors: a case report and review of the literature

BackgroundBeckwith–Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a variety of clinical features, including overgrowth and an increased risk of embryonal tumors. Notably however, reports of patients with BWS and breast tumors are rare, and the association between these conditions is still unclear. Insulin-like growth factor-2 (IGF2) expression is known to be associated with the development of various cancers, including breast cancer, and patients with BWS with specific subtypes of molecular defects are known to show characteristic clinical features and IGF2 overexpression.Case presentationA 17-year-old girl who had been diagnosed with BWS based on an umbilical hernia, hyperinsulinemia, and left hemihypertrophy at birth, visited our department with a gradually swelling left breast. Her left breast was markedly larger than her right breast on visual examination. Imaging examinations showed two tumors measuring about 10 cm each in the left breast, and she was diagnosed with juvenile fibroadenoma following core needle biopsy. The two breast tumors were removed surgically and the patient remained alive with no recurrence. The final diagnosis was juvenile fibroadenoma without malignant findings. Immunohistochemical staining using IGF2 antibody revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. Because of her clinical features and IGF2 overexpression, molecular defects of 11p15.5 including a possible genetic background of paternal uniparental disomy of chromosome 11 or hypermethylation of imprinting center 1 was suspected.ConclusionsIn this case, overexpression of IGF2 suggested a possible relationship between BWS and breast tumors. Moreover, the characteristic clinical features and IGF2 staining predicted the subtype of 11p15.5 molecular defects in this patient.

Prenatal diagnosis of paternal uniparental disomy for chromosome 2 in two fetuses with intrauterine growth restriction

Uniparental disomy (UPD) is when all or part of the homologous chromosomes are inherited from only one of the two parents. Currently, UPD has been reported to occur for almost all chromosomes. In this study, we report two cases of UPD for chromosome 2 (UPD2) encountered during prenatal diagnosis. The ultrasound findings of the fetuses from two unrelated families showed intrauterine growth restriction. The karyotype analyses were normal. The two fetuses both had complete paternal chromosome 2 uniparental disomy detected by whole-exome sequencing, but their clinical outcomes were significantly different, with fetal arrest in case 1 and birth in case 2. In this report, we analyzed and discussed the phenotypes of the fetuses in these two cases and reviewed the literature on UPD2.

Further understanding of paternal uniparental disomy Beckwith-Wiedemann syndrome

Introduction Paternal uniparental disomy of chromosome 11 (upd(11)pat) accounts for up to 20% of molecularly confirmed Beckwith-Wiedemann spectrum (BWSp) cases. It belongs to the BWSp subgroup with the second highest tumour risk, and therefore needs particular awareness in research, diagnostics and clinical management. Areas covered We overview the contribution of paternal (mosaic) uniparental disomy of chromosome 11 (UPD, upd(11)pat) and mosaic paternal uniparental diploidy in patients with Beckwith-Wiedemann features. The review comprises the current knowledge on their formation and their molecular and clinical consequences. Accordingly, the consequences for diagnostic testing and clinical monitoring are compiled. Expert opinion The necessity to diagnostically identify and thus discriminate genome-wide paternal uniparental disomy, and upd(11)pat becomes obvious, due to the differences in the clinical course, disease prognosis and treatment. In particular, monitoring of tumour development by liquid biopsy might be a promising option in the future. From the research point of view, it should be addressed why 11p is prone to mitotic recombination and thus also provide to the role of upd(11) as second hit in tumorigenesis.

First report of paternal uniparental disomy of chromosome 8 with SLC52A2 mutation in Brown-vialetto-van laere syndrome type 2 and an analysis of genotype-phenotype correlations.

Purpose: This study reports the clinical and genetic features of Brown-Vialetto-Van Laere syndrome (BVVL) type 2 in a case of uniparental disomy of chromosome 8 in mainland China and analyzes the genotype-phenotype correlation through a review of the literature of BVVL type 2 cases. Methods: The clinical characteristics, treatment, and follow-up data of the patient were summarized, and the etiology was identified by whole-exome sequencing and gene chip analysis. Correlations between the genotype and phenotype were analyzed by collecting clinical and genetic data of published cases and our patient. Results: We identified a homozygous mutation in SLC52A2 (NM_001253815.2 c.1255G>A) by trio-WES. Sanger sequencing confirmed that his father was heterozygous and his mother was wild type. Subsequently, paternal uniparental disomy of chromosome 8 [UPD (8)pat] was confirmed by chromosomal microarray analysis.The patient received long-term oral riboflavin treatment (7 mg/kg.d) and was followed up for 40 months by which time the child’s bulbar palsy, ataxia, and motor function had improved. A review of the literature and statistical analysis found that the symptoms of BVVL type 2 appear at the earliest shortly after birth and at the latest at 10 years of age. The median age of onset was 2.5 years, but the overall delay in diagnosis was a median of 5.6 years. The most common symptoms were hearing loss (83.9%), followed by muscle weakness (80.6%), visual impairment (64.5%), and ataxia (61.3%). To date, a total of 32 mutations in the SLC52A2 gene have been reported, with the most common being a missense mutation. Mutations occur throughout the length of the gene apart from at the N-terminus. In patients with missense mutations, homozygous pattern was more likely to present with ataxia as the first symptom (p < 0.05), while compound heterozygous pattern was more likely to develop respiratory insufficiency during the course of disease (p < 0.001). Moreover, patients with one missense mutation located in inside the transmembrane domain were more likely to have respiratory insufficiency than those with mutations both inside and outside the domain (p < 0.05). Riboflavin supplementation was an important factor in determining prognosis (p < 0.001). Conclusion: We report the first UPD(8)pat with SLC52A2 homozygous pathogenic mutation case in BVVL type 2, which expand the mutation spectrum of gene.

Paternal uniparental disomy of chromosome 16 resulting in homozygosity of a GPT2 mutation causes intellectual and developmental disability

Recessive mutations in glutamate pyruvate transaminase 2 (GPT2) have recently been found to be associated with intellectual and developmental disability (IDD). In this study, we discovered a homozygous missense variant, NM_133443: [c.1172C > T, p. Pro391Leu], of GPT2 on chromosome 16 in a proband diagnosed with IDD through trio whole-exome sequencing (WES). The pathogenicity of the variant was further verified by bioinformatics analysis and functional studies in vitro. This autosomal recessive disease was caused by paternal uniparental disomy (UPD) which was further proven by single nucleotide polymorphism array (SNP array). In past literature, recessive diseases in chromosome 16 were usually due to maternal UPD where Mendel's law of inheritance was not applicable. However, in our case we found that paternal UPD can cause recessive diseases related to the GPT2 gene on chromosome 16. Our study provides an important line of evidence for the diagnosis of GPT2-related intellectual developmental disorders.

Methylation analysis and developmental profile of two individuals with Angelman syndrome due to mosaic imprinting defects

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternally-inherited UBE3A on chromosome 15q11.2. In AS due to a chromosomal deletion that encompasses UBE3A, paternal uniparental disomy of chromosome 15, or imprinting defects (ImpD), the SNRPN locus is unmethylated, while in neurotypical individuals, it is ∼50% methylated. We present the developmental profile of two adults with mild AS assessed using standardized behavioral and neurodevelopmental measures. Both had intellectual disability with unusually advanced verbal communication skills compared to other individuals with AS. Methylation of the SNRPN locus was examined using Methylation Specific Quantitative Melt Analysis (MS-QMA) in different tissues at one time point for participant A (22 years) and two time points for participant B (T1: 22 years, T2: 25 years), and these levels were compared to a typical AS cohort. While participant A showed methylation levels comparable to the typical AS cohort, participant B showed methylation mosaicism in all tissues at both time points and changes in methylation levels from T1 to T2. AS should be considered in individuals with intellectual disability and verbal speech who may not have the typical symptoms of AS.

“Coat-hanger” ribs and Bell-Shaped Thorax in an Infant with Paternal Uniparental Disomy for Chromosome.

“Coat-hanger” ribs and Bell-Shaped Thorax in an Infant with Paternal Uniparental Disomy for Chromosome.

Транзиторный неонатальный сахарный диабет, ассоциированный с нарушением импринтинга хромосомы 6q24. Часть 2. Эпидемиология, этиология и патогенез

В статье описаны генетические варианты транзиторного неонатального сахарного диабета, указана частота встречаемости различных генетических дефектов у больных с синдромом 6q24-TNDM. Подробно представлены механизмы генетических нарушений, приводящих к развитию данного заболевания. Показано, что развитие 6q24-TNDM ассоциировано с отцовской однородительской дисомией по хромосоме 6, несбалансированной дупликацией q24 на копии отцовской хромосомы 6 и гипометилированием ICR на копии материнской хромосомы 6q24. Дефицит экспрессии гена фактора транскрипции PDX-1 играет важную роль в регенерации поджелудочной железы и дифференцировке β-клеток, а высокая скорость пролиферации и апоптоза клеток сопровождается нестабильностью равновесия продукции инсулина и потребности в нем. Указана роль протеина ZAC1 в патогенезе заболевания.

Beckwith–Wiedemann syndrome: Clinical, histopathological and molecular study of two Tunisian patients and review of literature

BackgroundBeckwith–Wiedemann syndrome (BWS) is a rare overgrowth syndrome characterized by congenital malformations and predisposition to embryonic tumors. Loss of methylation of imprinting center 2 (IC2) is the most frequent alteration and rarely associated with tumors compared to paternal uniparental disomy of chromosome 11 (UPD(11)pat) and gain of methylation of imprinting center 1.MethodsOur study aimed to describe the clinical, histopathological and genetic characteristics of two patients and establish genotype‐phenotype correlations. The clinical diagnosis was based on the criteria defined by the international expert consensus of BWS. Molecular study of 11p15.5 methylation status was assessed using methylation‐specific‐multiplex ligation probe amplification (MS‐MLPA).ResultsPatients were aged 12 months and 3 months and fulfilled the clinical score of BWS. MS‐MLPA showed molecular alterations consisting of loss of methylation in IC2 (IC2‐LOM) at the maternal allele for one patient and a mosaic UPD(11)pat for the second patient in whom follow‐up at 6months revealed adrenocortical carcinoma (ACC) with low grade of malignancy. Molecular subtypes guide the follow‐up and tumor surveillance, our major concern.ConclusionWe have to take into account the psychological impact of a possible tumor whatever the underlying mechanism is. Nevertheless, the tumor risk remains high for UPD(11)pat. Our study extended the phenotype of BWS with absence of macrosomia in Tunisian patients, contrasting with literature, and added a supplementary case of ACC in the tumor spectrum of BWS patients with UPD(11)pat.

Clinical, Genetic, and Prognostic Features of Adrenocortical Tumors in Children: A 10-Year Single-Center Experience.

Background and Aims: Pediatric adrenocortical tumors (ACTs) are very rare endocrine neoplasms in childhood. In this study, we performed a retrospective analysis of children with ACT treated at our institution by examining clinical and genetic disease features, treatment strategies, and outcomes.Methods: We retrospectively analyzed a cohort of 13 children treated at the Bambino Gesù Children's Hospital from November 2010 to March 2020.Results: The median age at diagnosis was 17 months (range = 0–82 months). The female: male ratio was 3.3/1. Mixed symptomatology (>1 hormone abnormality) was the most common presentation (46.1%). In three cases, the tumor was detected during prenatal or perinatal echographic screening. All patients presented with localized disease at diagnosis and underwent total adrenalectomy. Six patients were identified as having malignancies according to the Wieneke scoring system, five benign, and two undetermined. Seven patients underwent mitotane adjuvant therapy for 12 months. There was metastatic disease in three patients, with no correlation with age or Wieneke score. The most common sites of metastases were the liver and lungs. Metastatic patients were treated with surgery (n = 2), mitotane (n = 1), chemotherapy (n = 2) associated with anti-EGFR (n = 1), or immunotherapy with anti-PD1 (pembrolizumab) (n = 1); two patients achieved complete disease remission. Overall 2- and 5-year survival rates were 100%, with a median follow-up of 5 years (range = 2–9.5 years). Two- and 5-year disease free survival was 76.9 and 84.6%, respectively (95% confidence interval = −66.78–114.76 months). All patients are alive, 12 without disease, and one with stable disease. Genetic analyses showed TP53 germline mutations in six of eight patients analyzed (five inherited, one de novo). One patient had Beckwith–Wiedemann syndrome, with mosaic paternal uniparental disomy of chromosome 11, in both neoplastic and healthy adrenal tissue.Conclusion: We report the cases of 13 patients treated for ACT, including 12 aged <4 years at diagnosis, with a relative short time from symptoms onset. Our cohort experienced an excellent prognosis. TP53 mutation was found in 75% of tested patients (6/8) confirming the need to perform genetic tests and familial counseling in this disease.

Detection of copy number variants with chromosomal microarray in 10377 pregnancies at a single laboratory.

IntroductionInvasive prenatal testing with chromosomal microarray analysis may be a relevant option for all pregnant women, but there is only moderate‐quality evidence for such an offer. We intended to study the prevalence of copy number variants (CNVs) in prenatal samples using a single SNP‐array platform stratified by indication.Material and methodsA cross‐sectional study was performed based on a cohort. From January 2015 to December 2017, a total of 10 377 prenatal samples were received for prenatal single nucleotide polymorphism (SNP)‐array in the laboratory of the Genetics Generation Advancement Corporation. Indications for chromosomal microarray analysis studies included the confirmation of an abnormal karyotype, ultrasound abnormalities, advanced maternal age and parental anxiety. CNVs and region of homozygosity identified by the SNP‐array were analyzed.ResultsOf 10 377 cases, 689 had ultrasound abnormalities and 9688 were ascertained to have other indications. The overall prevalence of CNVs was 2.1% (n = 223/10 377, 95% confidence interval [CI] 1.9‐2.4), but the prevalence was 4.4% (95% CI 3.0‐6.1) for cases referred with abnormal ultrasound findings and 2.0% (95% CI 1.7‐2.3) for other indications. Of the 223 CNVs detected, 42/10 377 were pathogenic (0.4%, 95% CI 0.3‐0.6), 84 were susceptibility CNV (0.8%, 95% CI 0.6‐1.0) and 97 were variants of uncertain significance (0.9%, 95% CI 0.8‐1.1). Using an SNP‐based platform allowed for the detection of paternal uniparental disomy of chromosome 14 in a fetus with ultrasound abnormality.ConclusionsWith an indication of advanced maternal age but normal ultrasound scans, the prevalence of pathogenic CNVs was 0.4% and that of susceptibility CNV 0.7%. As CNVs are independent of maternal age, the prevalence is likely the same for younger women. Thus, this study provides further evidence that chromosomal microarray analysis should be available for all women who wish to receive diagnostic testing, as this risk is above the cut‐off of 1:300 for Down syndrome, leading to the suggestion of invasive testing. A chromosomal microarray analysis based on SNP‐array platform is preferable, as it can also detect uniparental disomy in addition to copy number variants.

Molecular-Genetic Diagnostics of Angelman Syndrome – The Bulgarian Experience

Abstract Objective: The aim of the study was to determine the molecular mechanisms of mutagenesis in Bulgarian patients with Angelman syndrome (AS). AS is a severe neurodevelopmental disorder caused by loss of expression in brain of the maternally inherited UBE3A gene as a result of various 15q11.2-q13 alterations. Material and Methods: In total 24 patients (11 boys, 13 girls) from 22 unrelated families with suspected clinical diagnosis AS were analysed. We used methylation specific PCR, multiplex ligation-dependent probe amplification, methylation sensitive MLPA, and direct sequencing of the UBE3A gene. Results: In 9 families (41%) pathogenic mutations were detected, which confirmed the clinical diagnosis on а molecular-genetic level. In 4 (44%) of these families we found 15q11-q13 region deletion with breakpoints BP1-BP3 or BP2-BP3. In 1 (11%) of the families we found imprinting defect: deletion of the AS-SRO regulatory region (part of the PWS-AS imprinting center). In 1 (11%) of the families we detected a rare finding – paternal uniparental disomy of chromosome 15. In 3 (33%) of the families diff erent point mutations in the UBE3A gene were detected: two novel missence mutations c.488T &gt; C; p.Leu163Ser and c.1832A &gt; T; p.Gln611Leu, and one known frameshift mutation c.2576_2579delAAGA; p.Lys859Argfs*4. Conclusion: The obtained results helped us to develop a systematic diagnostic algorithm in order to provide proper diagnosis for the patients with AS. Combining excellent knowledge of the molecular mechanisms of mutagenesis and proper molecular-genetic testing approaches is a cornerstone in the management of AS patients, ensuring AS families would receive both adequate genetic counseling and prophylaxis of the disease in the future.

Kagami-Ogata Syndrome: An Anomaly of the Ribs as a Pathognomonic Feature for the Clinical Diagnosis of an (epi)Genetic Syndrome

Within 4 years (2014-2017), we genetically diagnosed 2 newborns with Kagami-Ogata syndrome (OMIM #608149). As fetuses they exhibited prenatal polyhydramnios and in 1 case hepatomegaly. After birth, the newborns suffered from respiratory distress. Typical phenotypic features, such as muscular hypotonia, a protruding philtrum, full cheeks and a depressed nasal bridge, were present. Chest X-rays revealed coat-hanger ribs and a bell-shaped thorax, suggestive of the entity. Kagami-Ogata syndrome is caused by an aberrant gene expression of chromosome 14 and was first described in 1991. Possible causes are paternal uniparental disomy of chromosome 14, epimutations and microdeletions. Approximately 70 cases have been reported in the literature, with 34 comprising the original cohort of M. Kagami and T. Ogata. The incidence of the disease is unknown. Patients often manifest a developmental delay and an intellectual disability, although in the meantime cases with milder clinical courses have been described. In the cohort of Kagami and Ogata 3 patients developed hepatoblastoma, which is a common feature in another imprinting disorder, namely the Beckwith-Wiedemann syndrome. Therefore, hepatoblastoma should be considered in follow-up examinations.

Complete Paternal Uniparental Disomy of Chromosome 2 in an Asian Female Identified by Short Tandem Repeats and Whole Genome Sequencing

Uniparental disomy (UPD) is a rare type of chromosomal aberration that has sometimes been detected in paternity testing. We examined a 3-person family (father, mother, daughter) first by using short tandem repeat markers, which revealed 4 markers, TPOX, D2S1338, D2S1772, and D2S441, on chromosome 2 that were not transmitted in a Mendelian style. We then performed whole genome sequencing (WGS) to determine the range of the UPD. Chromosome 2 in the daughter showed a complete paternal UPD. To the best of our knowledge, this is the 4th case of complete paternal UPD of chromosome 2 with no clinical phenotype. Our study suggests that WGS, when performed to enhance the accuracy and reliability of parentage testing, can provide a powerful method to detect an UPD.

High frequency of paternal iso or heterodisomy at chromosome 20 associated with sporadic pseudohypoparathyroidism 1B.

Pseudohypoparathyroidism 1B (PHP1B) is caused by maternal epigenetic defects in the imprinted GNAS cluster. PHP1B can follow an autosomal dominant mode of inheritance or occur sporadically (spor-PHP1B). These latter patients present broad methylation changes of two or more differentially methylated regions (DMR) that, when mimicking the paternal allele, raises the suspicious of the occurrence of paternal uniparental disomy of chromosome 20 (upd(20)pat). A cohort of 33 spor-PHP1B patients was screened for upd(20)pat using comparative genomic hybridization with SNP-chip. Methylation analyses were assessed by methylation specific-multiplex ligation-dependent probe amplification. Upd(20)pat was identified in 6 patients, all exhibiting typical paternal methylation pattern compared to normal controls, namely a complete loss of methylation of GNAS A/B:TSS-DMR, negligible methylation at GNAS-AS1:TSS-DMR and GNAS-XL:Ex1-DMR and complete gain of methylation at GNAS-NESP:TSS-DMR. The overall frequency of upd(20) is 18% in our cohort when searched considering both severe and partial loss of imprinting. However, twenty five patients displayed severe methylation pattern and the upd(20)pat frequency reaches 24% when searching in this group. Consequently, up to day, upd(20)pat is the most common anomaly than other genetic alterations in spor-PHP1B patients. Upd(20)pat occurrence is not linked to the parental age in contrast to upd(20)mat, strongly associated with an advanced maternal childbearing age. This study provides criteria to guide further investigations for upd(20)pat needed for an adequate genetic counseling.

Identification of a rare homozygous &lt;i&gt;SZT2&lt;/i&gt; variant due to uniparental disomy in a patient with a neurodevelopmental disorder

Because biallelic SZT2 variants have been reported in patients with neurodevelopmental disorders associated with various degrees of developmental delay, intractable seizures, and distinctive features; this condition is recognized as an autosomal recessive disorder. Previously, eleven patients have been reported and most of them have compound heterozygous SZT2 variants, leading to premature termination. In these patients, all reported variants were unique and there were no common pathogenic variants identified. In this study, we identified a paternal uniparental disomy of chromosome 1 in a patient with a neurodevelopmental disorder associated with severe intellectual disability, intractable epilepsy, autistic features, distinctive features, and transient macrocephaly. This resulted in homozygous patterns through chromosome 1. Among the variants in chromosome 1, a rare SZT2 variant, NM_015284.3:c.6553C>T (p.Arg2185Trp), was selected as a powerful candidate variant in this patient. Although the clinical features of this patient are relatively milder than that reported previously, it may be derived from genetic heterogeneity. This is the first report of a homozygous missense SZT2 variant.

Prenatal diagnosis of two cases of paternal uniparental disomy of chromosome 6

To report on prenatal diagnosis and follow up of two patients with paternal uniparental disomy of chromosome 6 (pUPD6). Fetal cells were subjected to in situ culturing and G-banded chromosomal analysis. DNA samples of the fetuses and their parents were also analyzed with single nucleotide polymorphism microarray (SNP array). Both fetuses had a normal male karyotype. SNP array analysis showed both have carried pUPD6. pUPD6 can lead to transient neonatal diabetes mellitus type 1. Homozygous status of recessive mutations, disorder of gene imprinting, and its influence on placental function are the main factors to be considered during prenatal diagnosis and genetic counseling for pUPD6.

F179. Notched delta, epilepsy and Angelman’s syndrome genetics

Introduction Angelman syndrome (AS) is a neurogenetic disorder resulting from a deletion of the maternal 15q11.2-13.1 region, mutation of maternal UBE3A gene, paternal uniparental disomy of chromosome 15, or methylation imprinting defect. Epilepsy affects the majority of the patients. Notched delta (ND) is characterized by ill-defined mixed spikes among a diffuse delta slowing, giving a “notched” appearance seen in AS. The aim of this study was to evaluate the prevalence of ND and epilepsy among the known genetic mechanisms. Methods Patients with AS seen at the Mayo Clinic Medical Genetics Clinics between September 2006 and September 2017 were identified. Medical records were reviewed for epilepsy history and EEG findings. The first 4 available EEG reports were reviewed for presence of ND. Patients were classified into 4 genetic groups: 1. microdeletion, 2.uniparental disomy (UPD), 3.UBE3A mutation, or 4.methylation defect. Patients without research consent (n = 1), inadequate epilepsy or EEG records (n = 3) were excluded. The age at seizure onset and the prevalence of ND was calculated in each genetic group. Fisher exact tests and nonparametric Wilcoxon rank sum test were used. Results Twenty-four patients were included (male 42%, median age 14.1 years, IQR 8.4–25.8). Genetic etiology was microdeletion 13, UPD 1, UBE3A mutation 4, and methylation defect 6. Epilepsy was present in 21/24 (88%) patients. There was no difference in the prevalence of epilepsy among the different genetic groups (microdeletion 12/13, UPD 1/1, UBE3A mutation 3/4, methylation defect 5/6, p > 0.05). Patients without seizure were younger than those with epilepsy (No seizure median age 7.4 years, IQR 2.6–8.4 vs Epilepsy 17.3 years, IQR 9.6–27.5, p = 0.03). Among epilepsy patients, the median age of seizure onset was 2 years, IQR 0.5–3.7. Patients with microdeletion have earlier age of seizure onset compared to the other groups: microdeletion, n = 12, median age of seizure onset 1.3 years, IQR 0.5–2.0; UPD, n = 1, age of seizure onset 3.0 years; UBE3A mutation, n = 3, median age of seizure onset 4.3 years, IQR 2.7–5.2; methylation defect, n = 5, median age of seizure onset, 3.8 years IQR 1.7–5.1; p = 0.03. ND was recognized in 15/24 (62%) patients at any time, including 8/13 chromosomal microdeletion, 1/1 UPD, 2/4 UBE3A mutation, 4/6 methylation defect. The median age at which ND was first recognized was 9.2 years, IQR 2.83–18.2. Prevalence of epilepsy was no different between patients with or without ND (13/15 patient ND and 8/9 patients without ND, p > 0.05). Conclusion Epilepsy was invariably present in the majority of the different genetic groups of AS patients, with earlier age of onset in the chromosome 15 microdeletion group. Patients with seizures were older than those without which may suggest an age related increased risk for developing epilepsy. ND was recognized in nearly two-thirds of all patients, with no specific distribution among the different genetic etiologies and did not influence the prevalence of epilepsy.

Angelman syndrome - insights into a rare neurogenetic disorder.

Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman syndrome results from loss of function of the imprinted UBE3A (ubiquitin-protein ligase E3A) gene on chromosome 15q11.2-q13. This loss of function can be caused by a mutation on the maternal allele, a 5-7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect. The chromosomal deletion tends to cause the most severe symptoms, possibly owing to co-deletion of GABA receptor genes. UBE3A mutations and imprinting defects can be associated with a high risk of recurrence within families. Disruption of UBE3A function in neurons seems to inhibit synapse formation and experience-dependent synapse remodelling. Clinical diagnosis of Angelman syndrome in infants and young children is sometimes difficult, but can be verified by genetic tests. At present, treatment of symptoms such as seizures is the only medical strategy, but genetic therapies aimed at activating the silent copy of UBE3A on the paternal allele are conceivable.

Paternal uniparental disomy with segmental loss of heterozygosity of chromosome 11 are hallmark characteristics of syndromic and sporadic embryonal rhabdomyosarcoma.

Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS. We characterized eleven ERMS tumors from eight unrelated CS patients, carrying paternally derived HRAS c.34G>A (p.Gly12Ser; 6) or c.35G>C (p.Gly12Ala; 2) mutations. Loss of heterozygosity (LOH) was evaluated in all CS ERMS by microarray and/or short tandem repeat (STR) markers spanning the entire chromosome 11. Eight CS ERMS tumors displayed complete paternal uniparental disomy of chromosome 11 (pUPD11), whereas two displayed UPD only at 11p and a second primary ERMS tumor showed UPD limited to 11p15.5, the classical hallmark for ERMS. Three sporadic ERMS cell lines (RD, Rh36, Rh18) and eight formalin fixed paraffin embedded (FFPE) ERMS tumors were also analyzed for RAS mutations and LOH status. We found a higher than anticipated frequency of RAS mutations (HRAS or NRAS; 50%) in sporadic ERMS cell lines/tumors. Unexpectedly, complete uniparental disomy (UPD11) was observed in five specimens, while the other six showed LOH extending across the p and q arms of chromosome 11. In this study, we are able to clearly demonstrate complete UPD11 in both syndromic and sporadic ERMS. © 2016 Wiley Periodicals, Inc.