scholarly journals Clinical-neurologic, cytogenetic and molecular aspects of the Prader-Willi and Angelman Syndromes

1997 ◽  
Vol 55 (2) ◽  
pp. 199-208 ◽  
Author(s):  
João M. de Pina-Neto ◽  
Victor Evangelista F. Ferraz ◽  
Greice Andreotti de Molfetta ◽  
Jess Buxton ◽  
Sarah Richards ◽  
...  
Keyword(s):  
De Novo ◽  
Cpg Island ◽  
Chromosome Region ◽  
Uniparental Disomy ◽  
Restriction Enzymes ◽  
University Hospital ◽  
Chromosome 15 ◽  
Maternal Chromosome ◽  
Conventional Cytogenetics ◽  
Cytogenetical Analysis

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are human neurogenetic disorders involving the imprinting mechanism, at the 15q11-13 chromosome region. The predominant genetic defects in PW are 15q 11-13 deletions of paternal origin and maternal chromosome 15 uniparental disomy. In contrast, maternal deletions and paternal chromosome 15 uniparental disomy are associated with a different neurogenetic disorder, the AS. In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q 11-13 loci. We studied 5 patients suspect of PWS and 4 patients suspect of AS who were referred to the Medical Genetics Unit at the University Hospital of Medical School from Ribeirão Preto. Our objective was to establish the correct clinical and etiological diagnosis in these cases. We used conventional cytogenetics, methylation analysis with the probe KB 17 (CpG island of the SNRPN gene) by Southern blotting after digestion with the Xba I and Not I restriction enzymes. We studied in patients and their parents the segregation of the (CA)n repeats polymorphisms by PCR, using the primers 196 and IR4-3R. All the patients had normal conventional cytogenetical analysis. We confirmed 3 cases of PWS: one by de novo deletion, one by maternal chromosome 15 uniparental disomy and one case with no defined cause determined by the used primers. We confirmed 2 cases of AS, caused by de novo deletion at the 15q 11-13 region, and one case with normal molecular analysis but with strong clinical characteristics.

scholarly journals Dosage and Imprinting Effects in Abnormalities of Human Chromosome 15

1996 ◽  
Vol 45 (1-2) ◽  
pp. 83-83 ◽  
Author(s):  
D.H. Ledbetter ◽  
S.L. Christian ◽  
T. Kubota ◽  
A. Mutirangura ◽  
J.S. Sutcliffe ◽  
...  
Keyword(s):  
Yeast Artificial Chromosome ◽  
Cpg Island ◽  
Uniparental Disomy ◽  
Artificial Chromosome ◽  
Chromosome 15 ◽  
Diagnostic Strategy ◽  
Str Analysis ◽  
Paternal Grandmother ◽  
Cosmid Contigs ◽  
Yac Contig

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders caused by paternal deficiency (PWS) or maternal deficiency (AS) of gene(s) in 15qll.2-ql3. We have constructed a 3.5 Mb yeast artificial chromosome (YAC) contig of the PWS/AS region and cosmid contigs of selected YACs at D15S13, SNRPN, S10, and S113. Cosmid clones have been used for fluorescence in situ hybridization (FISH) detection of deletions in PWS and AS patients. In addition, a total of 28 short tandem repeat polymorphisms (STRs) have been mapped to specific YACs in the contig, providing a highly informative set of markers for detection of deletion or uniparental disomy (UPD) in PWS and AS patients. Use of the 3 most informative markers in this region (S542, S128, and ASSCA-1) plus 3 markers distal on 15q (S123, S125, and S131) provide an efficient diagnostic strategy for UPD15.A combination of FISH and STR analysis has identified small deletions in one sporadic and one familial case of PWS (family O). Both deletions involve all or part of the SNRPN gene but do not extend telomeric to PAR-5 or PAR-1, two novel transcripts expressed exclusively from the paternal chromosome. However, expression of SNRPN, PAR-5, and PAR-1 is lost in both cases, implying the presence of an imprinting control region near SNRPN. The smallest deletion in family O is estimated at approximately 30-40 kb in size and involves a newly identified CpG island at the 5′ end of SNRPN which is methylated on the maternal chromosome. This small deletion in two PWS affected siblings was present in the father and the paternal grandmother, both of whom were phenotypically normal.

Angelman Syndrome-Affected Individual with a Numerically Normal Karyotype and Isodisomic Paternal Uniparental Disomy of Chromosome 15 due to Maternal Robertsonian Translocation (14;15) by Monosomy Rescue

2018 ◽  
Vol 156 (1) ◽  
pp. 9-13 ◽  
Author(s):  
Nuria C. Bramswig ◽  
Karin Buiting ◽  
Natalie Bechtel ◽  
Bernhard Horsthemke ◽  
Kevin Rostasy ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Robertsonian Translocation ◽  
Chromosome Region ◽  
Neurodevelopmental Disorder ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
Early Embryo ◽  
Affected Individual ◽  
Chromosome 15 ◽  
Paternal Uniparental Disomy

Angelman syndrome (AS) is a neurodevelopmental disorder caused by deletion of the maternally inherited 15q11q13 region, paternal uniparental disomy 15 [upd(15)pat], an imprinting defect of the maternal chromosome region 15q11q13, or a pathogenic mutation of the maternal UBE3A allele. Predisposing factors for upd(15)pat, such as nonhomologous robertsonian translocation involving chromosome 15, have been discussed, but no evidence for this predisposition has been published. In the present study, chromosomal analysis was performed in a child with AS, both parents, and the maternal grandparents. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was employed on DNA of the index individual, and microsatellite analysis was carried out on DNA of the index individual and his parents. The cytogenetic analysis showed that the mother and maternal grandfather are carriers of a rob(14;15). The index individual has a numerically normal karyotype, but MS-MLPA and microsatellite analyses confirmed the clinical diagnosis of AS and revealed a pattern highly suggestive of isodisomic upd(15)pat. This is the first report of an AS-affected individual with isodisomic upd(15)pat and a numerically normal karyotype that most likely results from a rob(14;15)-associated meiotic error in the maternal germline followed by monosomy 15 rescue in the early embryo.

Deletion and Uniparental Disomy Involving the Same Maternal Chromosome 15

1994 ◽  
Vol 330 (8) ◽  
pp. 572-573 ◽  
Author(s):  
Linda C. Surh ◽  
Hungshu Wang ◽  
Alasdair G.W. Hunter
Keyword(s):  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Maternal Chromosome

scholarly journals Molecular Diagnosis of Prader–Willi and Angelman Syndromes by Methylation-Specific Melting Analysis and Methylation-Specific Multiplex Ligation-Dependent Probe Amplification

2006 ◽  
Vol 52 (7) ◽  
pp. 1276-1283 ◽  
Author(s):  
Melinda Procter ◽  
Lan-Szu Chou ◽  
Wei Tang ◽  
Mohamed Jama ◽  
Rong Mao
Keyword(s):  
Chromosome Region ◽  
Uniparental Disomy ◽  
Rapid Screening ◽  
Parental Origin ◽  
Chromosome 15 ◽  
Imprinting Center ◽  
Melting Analysis ◽  
Methylation Patterns ◽  
Dependent Probe

Abstract Background: Approximately 99% of Prader–Willi syndrome (PWS) and 80% of Angelman syndrome (AS) cases have deletions at a common region in chromosome 15q11.2-q13, uniparental disomy for chromosome 15 (UPD15), or imprinting center defects affecting gene expression in this region. The resulting clinical phenotype (PWS or AS) in each class of genomic abnormalities depends on the parent of origin. Both disorders are characterized at the molecular level by abnormal methylation of imprinted regions at 15q11.2-q13. Other rare chromosome 15 rearrangements and a few smaller atypical deletions associated with abnormal methylation patterns also have symptoms overlapping with either PWS or AS. Methods: We designed a methylation-specific melting analysis (MS-MA) method for a rapid screening of PWS/AS and evaluated methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for diagnosis of PWS/AS associated with deletions, UPD15, or rare duplications. Forty-nine previously genotyped samples were tested by MS-MA. We also tested 26 MS-MA genotyped samples and 1 additional sample with rare duplication of chromosome region 15q11-q12. Results: PWS/AS genotyping results obtained by MS-MA and by MS-MLPA were fully concordant. In addition, MS-MLPA was superior in detecting deletions/rare duplications, possible UPD15, or imprinting center defects, which were usually determined by a laborious fluorescence in situ hybridization method or by chromosomal segregation analysis for the parental-origin using short-tandem repeat makers. Conclusions: MS-MA appears to be an efficient primary method to diagnose PWS/AS, and use of the quantitative MS-MLPA method provides detailed information about deletions, rare duplications, and possibly UPD.

scholarly journals Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Henrik Stranneheim ◽  
Kristina Lagerstedt-Robinson ◽  
Måns Magnusson ◽  
Malin Kvarnung ◽  
Daniel Nilsson ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
De Novo ◽  
Genomic Medicine ◽  
Uniparental Disomy ◽  
Healthcare Setting ◽  
University Hospital ◽  
Whole Genome ◽  
Number Of Patients

Abstract Background We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting. Methods Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout—a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams. Results Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange. Conclusions Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.

Recurrent meiotic nondisjunction of maternal chromosome 15 in a sibship

1998 ◽  
Vol 76 (1) ◽  
pp. 103-104 ◽  
Author(s):  
Jean-Paul Harpey ◽  
Delphine Heron ◽  
Muriel Prudent ◽  
Sylvie Lesourd ◽  
Isabelle Henry ◽  
...  
Keyword(s):  
Chromosome 15 ◽  
Maternal Chromosome ◽  
Meiotic Nondisjunction

Construction of individual ddRAD libraries v2

2021 ◽  
Author(s):  
Claire Daguin Thiebaut ◽  
Stephanie Ruault ◽  
Charlotte Roby ◽  
Thomas Broquet ◽  
Frédérique Viard ◽  
...  
Keyword(s):  
Magnetic Beads ◽  
Sex Chromosome ◽  
De Novo ◽  
Pcr Amplification ◽  
Restriction Enzymes ◽  
Tree Frog ◽  
Size Selection ◽  
Hyla Arborea ◽  
Sequencing Method ◽  
Sample Representation

This protocol describes a double digested restriction-site associated DNA (ddRADseq) procedure, that is a variation on the original RAD sequencing method (Davey & Blaxter 2011), which is used for de novo SNP discovery and genotyping. This protocol differs from the original ddRADseq protocol (Peterson et al 2012), in which the samples are pooled just after the ligation to adaptors (i.e. before size selection and PCR). The present ddRAD protocol as been slightly adapted from Alan Brelsford's protocol published in the supplementary material of this paper: Brelsford, A., Dufresnes, C. & Perrin, N. 2016. High-density sex-specific linkage maps of a European tree frog (Hyla arborea) identify the sex chromosome without information on offspring sex. Heredity 116, 177–181 (2016). https://doi.org/10.1038/hdy.2015.83 In the present protocol, all samples are treated separately, in a microplate, until final PCR amplification performed before pooling. Despite being slightly more costly and time-consuming in the lab, it allows for fine adjustement of each sample representation in the final library pool, ensuring similar number of sequencing reads per sample in the final dataset. Briefly, genomic DNA from the samples are individually digested with 2 restriction enzymes (one rare-cutter and one more frequent cutter) then ligated to a barcoded adaptor (among 24 available) at one side, and a single adaptor at the other side, purified with magnetic beads, and PCR-amplified allowing the addition of a Illumina index (among 12 available) for multiplexing a maximum of 288 sample per library. Samples are then pooled in equimolar conditions after visualisation on an agarose gel. Purification and size selection is then performed before final quality control of the library and sequencing.

A Case of Angelman Syndrome Arising as a Result of a De Novo Robertsonian Translocation

1996 ◽  
Vol 45 (1-2) ◽  
pp. 255-261 ◽  
Author(s):  
S. Ramsden ◽  
L. Gaunt ◽  
A. Seres-Santamaria ◽  
J. Clayton-Smith
Keyword(s):  
Angelman Syndrome ◽  
Robertsonian Translocation ◽  
De Novo ◽  
Uniparental Disomy ◽  
Male Child ◽  
Paternal Uniparental Disomy

AbstractA male child has been identified with Angelman syndrome. He has been shown to carry a de novo Robertsonian 15/15 translocation where both chromosome 15s have been derived from the father. Consequently the disease in this instance is due to paternal uniparental disomy.

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