scholarly journals PWS/AS MS-MLPA Confirms Maternal Origin of 15q11.2 Microduplication

2015 ◽  
Vol 2015 ◽  
pp. 1-3 ◽  
Author(s):  
Angelika J. Dawson ◽  
Janice Cox ◽  
Karine Hovanes ◽  
Elizabeth Spriggs
Keyword(s):  
De Novo ◽  
Clinical Phenotype ◽  
Methylation Status ◽  
Uniparental Disomy ◽  
Proximal Region ◽  
Parental Origin ◽  
Developmental Abnormalities ◽  
Genomic Array ◽  
Parent Of Origin ◽  
Dependent Probe

The proximal region of the long arm of chromosome 15q11.2-q13 is associated with various neurodevelopmental disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes, autism, and other developmental abnormalities resulting from deletions and duplications. In addition, this region encompasses imprinted genes that cause PWS or AS, depending on the parent-of-origin. This imprinting allows for diagnosis of PWS or AS based on methylation status using methylation sensitive (MS) multiplex ligation dependent probe amplification (MLPA). Maternally derived microduplications at 15q11.2-q13 have been associated with autism and other neuropsychiatric disorders. Multiple methods have been used to determine the parent-of-origin for 15q11.2-q13 microdeletions and microduplications. In the present study, a four-year-old nondysmorphic female patient with developmental delay was found to have ade novo~5 Mb duplication within 15q11.2 by oligonucleotide genomic array. In order to determine the significance of this microduplication to the clinical phenotype, the parent-of-origin needed to be identified. The PWS/AS MS-MLPA assay is generally used to distinguish between deletion and uniparental disomy (UPD) of 15q11.2-q13, resulting in either PWS or AS. However, our study shows that PWS/AS MS-MLPA can also efficiently distinguish the parental origin of duplications of 15q11.2-q13.

scholarly journals Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors

2015 ◽  
Vol 22 (6) ◽  
pp. 953-967 ◽  
Author(s):  
Helene Myrtue Nielsen ◽  
Alexandre How-Kit ◽  
Carole Guerin ◽  
Frederic Castinetti ◽  
Hans Kristian Moen Vollan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Methylation Status ◽  
Uniparental Disomy ◽  
Copy Number Variations ◽  
Conclusive Evidence ◽  
Adrenal Tumors ◽  
Benign Tumors ◽  
Parental Origin ◽  
Adrenocortical Carcinomas

Overexpression of insulin growth factor 2 (IGF2) is a hallmark of adrenocortical carcinomas and pheochromocytomas. Previous studies investigating the IGF2/H19 locus have mainly focused on a single molecular level such as genomic alterations or altered DNA methylation levels and the causal changes underlying IGF2 overexpression are still not fully established. In the current study, we analyzed 62 tumors of the adrenal gland from patients with Conn's adenoma (CA, n=12), pheochromocytomas (PCC, n=10), adrenocortical benign tumors (ACBT, n=20), and adrenocortical carcinomas (ACC, n=20). Gene expression, somatic copy number variation of chr11p15.5, and DNA methylation status of three differential methylated regions of the IGF2/H19 locus including the H19 imprinting control region were integratively analyzed. IGF2 overexpression was found in 85% of the ACCs and 100% of the PCCs compared to 23% observed in CAs and ACBTs. Copy number aberrations of chr11p15.5 were abundant in both PCCs and ACCs but while PCCs retained a diploid state, ACCs were frequently tetraploid (7/19). Loss of either a single allele or loss of two alleles of the same parental origin in tetraploid samples resulted in a uniparental disomy-like genotype. These copy number changes correlated with hypermethylation of the H19 ICR suggesting that the lost alleles were the unmethylated maternal alleles. Our data provide conclusive evidence that loss of the maternal allele correlates with IGF2 overexpression in adrenal tumors and that hypermethylation of the H19 ICR is a consequence thereof.

scholarly journals Maternal Uniparental Disomy for Chromosome 14

1996 ◽  
Vol 45 (1-2) ◽  
pp. 169-172 ◽  
Author(s):  
D.A. Coviello ◽  
E. Panucci ◽  
M.M. Mantero ◽  
C. Perfumo ◽  
M. Guelfi ◽  
...  
Keyword(s):  
Robertsonian Translocation ◽  
De Novo ◽  
Clinical Phenotype ◽  
Uniparental Disomy ◽  
Chromosome 14 ◽  
Motor Delay ◽  
Maternal Uniparental Disomy ◽  
Severe Scoliosis ◽  
Severe Hypotonia

AbstractA girl carrying a de novo balanced 13-14 robertsonian translocation showed a clinical phenotype with severe hypotonia, hyperextensible joints, frontal bossing, asymmetric face, no mental retardation, severe scoliosis and motor delay. In situ hybridization analysis on chromosome spreads revealed the presence of the two centromeres in the rearranged chromosomes. Molecular analysis on genomic DNA showed the presence in the proposita of two chromosomes 14 of maternal origin and no chromosome 14 from the father indicating a maternal monocentric uniparental disomy for chromosome 14 (mUPD14). Our patient shows several similarities with other reported cases of mUPD14, suggesting imprinting of a region(s) of chromosome 14 and defining a possible mUPD14 Syndrome.

Angelman Syndrome Caused by Chromosomal Rearrangements: A Case Report of 46,XX,+der(13)t(13;15)(q14.1;q12)mat,-15 with an Atypical Phenotype and Review of the Literature

2016 ◽  
Vol 149 (4) ◽  
pp. 247-257
Author(s):  
Yo Niida ◽  
Hitoshi Sato ◽  
Mamoru Ozaki ◽  
Masatsune Itoh ◽  
Kanju Ikeno ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
De Novo ◽  
Chromosomal Rearrangements ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Parental Origin ◽  
Review Of The Literature ◽  
Balanced Translocation ◽  
Multicolor Fish ◽  
Partial Monosomy

Less than 1% of the cases with Angelman syndrome (AS) are caused by chromosomal rearrangements. This category of AS is not well defined and may manifest atypical phenotypes. Here, we report a girl with AS due to der(13)t(13;15)(q14.1;q12)mat. SNP array detected the precise deletion/duplication points and the parental origin of the 15q deletion. Multicolor FISH confirmed a balanced translocation t(13;15)(q14.1;q12) in her mother. Her facial appearance showed some features of dup(13)(pter→q14). Also, she lacked the most characteristic and unique behavioral symptoms of AS, i.e., frequent laughter, happy demeanor, and easy excitability. A review of the literature indicated that AS cases caused by chromosomal rearrangements can be classified into 2 major categories and 4 groups. The first category is paternal uniparental disomy 15, which is subdivided into isodisomy by de novo rob(15;15) and heterodisomy caused by paternal translocation. The second category is the deletion of the AS locus due to maternal reciprocal translocation, which is subdivided into 2 groups associated with partial monosomy by 3:1 segregation and partial trisomy by adjacent-2 segregation. Classification into these categories facilitates the understanding of the mechanisms of chromosomal rearrangements and helps in accurate diagnosis and genetic counseling of these rare forms of AS.

scholarly journals Sex-specific recombination predicts parent of origin for recurrent genomic disorders

2020 ◽  
Author(s):  
Trenell Mosley ◽  
H. Richard Johnston ◽  
David J Cutler ◽  
Michael E Zwick ◽  
Jennifer G Mulle
Keyword(s):  
Large Scale ◽  
Structural Variation ◽  
De Novo ◽  
Copy Number Variants ◽  
Parental Origin ◽  
Structural Rearrangements ◽  
Recombination Rates ◽  
Pathogenic Cnvs ◽  
Parent Of Origin ◽  
Genomic Disorders

Abstract Genomic disorders are caused by structural rearrangements of the genome that generally occur during meiosis. Often the rearrangements result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb). Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. Here we have curated parent of origin data for multiple pathogenic CNV loci and demonstrate a significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci. Our results suggest that parental-origin of CNVs is largely controlled by sex-specific recombination rates, and highlight the need to consider these differences when investigating mechanisms that cause structural variation.

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 Sex-specific recombination predicts parent of origin for recurrent genomic disorders

2020 ◽  
Author(s):  
Trenell Mosley ◽  
H. Richard Johnston ◽  
David J. Cutler ◽  
Michael E. Zwick ◽  
Jennifer G. Mulle
Keyword(s):  
Large Scale ◽  
Structural Variation ◽  
De Novo ◽  
Copy Number Variants ◽  
Parental Origin ◽  
Recombination Rates ◽  
Pathogenic Cnvs ◽  
Parent Of Origin ◽  
Genomic Disorders ◽  
Underlying Risk

SUMMARYGenomic disorders are caused by structural rearrangements of the genome that generally occur during meiosis1. Often the rearrangements result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb)2,3. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR)3,4. Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs5–9. However, the mechanism underlying these biases is not well understood. Here we have curated parent of origin data for multiple pathogenic CNV loci and demonstrate a significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci. Our results suggest that parental-origin of CNVs is largely controlled by sex-specific recombination rates and bring into light the need to consider these differences when seeking to determine the factors underlying risk for structural variation.

Mosaic de novo SNRPN gene variant associated with Prader-Willi syndrome

2021 ◽  
pp. jmedgenet-2020-107674
Author(s):  
Yue Huang ◽  
Katheryn Grand ◽  
Virginia Kimonis ◽  
Merlin G Butler ◽  
Suparna Jain ◽  
...  
Keyword(s):  
Sleep Disturbances ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Uniparental Disomy ◽  
Methylation Pattern ◽  
Parental Origin ◽  
Prader Willi Syndrome ◽  
Single Nucleotide ◽  
Imprinting Disorder ◽  
First Case

BackgroundPrader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects.ResultsWe report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant.ConclusionsThis is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS.

scholarly journals Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Trenell J. Mosley ◽  
H. Richard Johnston ◽  
David J. Cutler ◽  
Michael E. Zwick ◽  
Jennifer G. Mulle
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Copy Number Variants ◽  
Parental Origin ◽  
Recombination Rates ◽  
Pathogenic Cnvs ◽  
Parent Of Origin ◽  
Genomic Disorders ◽  
The Relationship ◽  
Male To Female

Abstract Background Structural rearrangements of the genome, which generally occur during meiosis and result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb), underlie genomic disorders. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. Methods We performed a systematic, comprehensive literature search to curate parent of origin data for multiple pathogenic CNV loci. Using a regression framework, we assessed the relationship between parental CNV origin and the male to female recombination rate ratio. Results We demonstrate significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci (p = 1.07 × 10–14). Conclusions Our results suggest that parental origin of CNVs is largely influenced by sex-specific recombination rates and highlight the need to consider these differences when investigating mechanisms that cause structural variation.

Copper-Induced Epigenetic Changes Shape the Clinical Phenotype in Wilson Disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Daniela Fanni ◽  
Clara Gerosa ◽  
Valeria Marina Nurchi ◽  
Rosita Cappai ◽  
Marta Mureddu ◽  
...  
Keyword(s):  
Wilson Disease ◽  
Clinical Presentation ◽  
Clinical Phenotype ◽  
Methylation Status ◽  
Copper Metabolism ◽  
Epigenetic Factors ◽  
Genetic Changes ◽  
Illness Onset ◽  
Phenotypic Manifestation ◽  
Copper Overload

: Wilson disease is a congenital disorder of copper metabolism whose pathogenesis remains, al least in part, unknown. Subjects carrying the same genotype may show completely different phenotypes, differing for the age at illness onset or for the hepatic, neurologic or psychiatric clinical presentation. The inhability to find a unequivocal correlation between the type of mutation in the ATPase copper transporting beta (ATP7B) gene and the phenotypic manifestation, induced many authors to look for epigenetic factors interacting with the genetic changes. Here the evidences regarding the ability of copper overload to change the global DNA methylation status are discussed.

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