The chromosome 15 imprinting centre (IC) region has undergone multiple duplication events and contains an upstream exon of SNRPN that is deleted in all Angelman syndrome patients with an IC microdeletion

Abstract Background: Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are 2 distinct neurodevelopmental disorders caused primarily by deficiency of specific parental contributions at an imprinted domain within the chromosomal region 15q11.2-13. In most cases, lack of paternal contribution leads to PWS either by paternal deletion (∼70%) or maternal uniparental disomy (UPD; ∼30%). Most cases of AS result from the lack of a maternal contribution from this same region by maternal deletion (∼70%) or by paternal UPD (∼5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus can differentiate the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS. Methods: Sodium bisulfite–treated genomic DNA was PCR-amplified for the SNRPN gene. We used pyrosequencing to individually quantify the resulting artificial C/T sequence variation at CpG sites. Anonymized DNA samples from PWS patients (n = 40), AS patients (n = 31), and controls (n = 81) were analyzed in a blinded fashion with 2 PCR and 3 pyrosequencing reactions. We compared results from the pyrosequencing assays with those obtained with a commonly used methylation-specific PCR (MS-PCR) diagnostic protocol. Results: The pyrosequencing assays had a sensitivity and specificity of 100% and provided quantification of methylation at 12 CpG sites within the SNRPN locus. The resulting diagnoses were 100% concordant with those obtained from the MS-PCR protocol. Conclusions: Pyrosequencing is a rapid and robust method for quantitative methylation analysis of the SNRPN locus and can be used as a diagnostic test for PWS and AS.

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A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics

Frontiers in Genetics ◽

10.3389/fgene.2021.608889 ◽

2021 ◽

Vol 12 ◽

Author(s):

Samuel P. Strom ◽

Waheeda A. Hossain ◽

Melina Grigorian ◽

Mickey Li ◽

Joseph Fierro ◽

...

Keyword(s):

Angelman Syndrome ◽

Genetic Defect ◽

Point Mutations ◽

High Sensitivity ◽

Standard Of Care ◽

Disease Diagnosis ◽

Genetic Alterations ◽

Chromosome 15 ◽

Current Standard ◽

Care Technology

Establishing or ruling out a molecular diagnosis of Prader–Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic alterations that can lead to these conditions. Point mutations, copy number changes, uniparental isodisomy (i-UPD) 15 of two subclasses (segmental or total isodisomy), uniparental heterodisomy (h-UPD), and defects in the chromosome 15 imprinting center can all cause PWS/AS. Here, we outline a combined approach using whole-exome sequencing (WES) and DNA methylation data with methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) to establish both the disease diagnosis and the mechanism of disease with high sensitivity using current standard of care technology and improved efficiency compared to serial methods. The authors encourage the use of this approach in the clinical setting to confirm and establish the diagnosis and genetic defect which may account for the secondary genetic conditions that may be seen in those with isodisomy 15, impacting surveillance and counseling with more accurate recurrence risks. Other similarly affected individuals due to other gene disorders or cytogenetic anomalies such as Rett syndrome or microdeletions would also be identified with this streamlined approach.

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Blended phenotype of AP4E1 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15

Brain and Development ◽

10.1016/j.braindev.2019.12.008 ◽

2020 ◽

Vol 42 (3) ◽

pp. 289-292 ◽

Cited By ~ 1

Author(s):

Hiroaki Murakami ◽

Tomoko Uehara ◽

Yoshinori Tsurusaki ◽

Yumi Enomoto ◽

Yukiko Kuroda ◽

...

Keyword(s):

Angelman Syndrome ◽

Chromosome 15

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A patient with a supernumerary marker chromosome (15), Angelman syndrome, and uniparental disomy resulting from paternal meiosis II non-disjunction

Journal of Medical Genetics ◽

10.1136/jmg.39.2.e9 ◽

2002 ◽

Vol 39 (2) ◽

pp. 9e-9 ◽

Cited By ~ 9

Author(s):

S Roberts

Keyword(s):

Angelman Syndrome ◽

Marker Chromosome ◽

Uniparental Disomy ◽

Chromosome 15

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Molecular Analysis of an Extra inv dup(15)(q13) Chromosome in Two Patients with Angelman Syndrome

Acta geneticae medicae et gemellologiae twin research ◽

10.1017/s0001566000001331 ◽

1996 ◽

Vol 45 (1-2) ◽

pp. 217-220 ◽

Cited By ~ 2

Author(s):

T. Buchholz ◽

S. Schuffenhauer ◽

K. Evans ◽

L. Robson ◽

B. Appleton ◽

...

Keyword(s):

Molecular Analysis ◽

Angelman Syndrome ◽

Uniparental Disomy ◽

Molecular Data ◽

Monoallelic Expression ◽

Chromosome 15 ◽

Prader Willi Syndrome ◽

Loss Of Function ◽

Maternal Allele ◽

Molecular Defects

Angelman syndrome (AS) is caused by the loss of function of yet unidentified gene(s) which map within 15q 11-13 and show monoallelic expression from the maternal allele. Lack of the maternal allele(s), due to either a deletion on the maternal chromosome 15 (about 70% of AS patients) or a paternal uniparental disomy (UPD)15 (<5%), are the most common molecular defects in AS. Prader-Willi syndrome (PWS) also maps to proximal 15q, but is caused by the loss of function of paternally expressed gen(s) [1]. Here we describe clinical, cytogenetic and molecular data for two non-related patients with AS who carry a nonmosaic extra cromosome inv dup(15).

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Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.62371 ◽

2021 ◽

Author(s):

Kimiko Ueda ◽

Satoru Ogawa ◽

Keiko Matsuda ◽

Yuiko Hasegawa ◽

Eriko Nishi ◽

...

Keyword(s):

Angelman Syndrome ◽

Chromosome 15

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Characterization of the structure and evolution of the Adh region of Drosophila hydei.

Genetics ◽

10.1093/genetics/127.2.355 ◽

1991 ◽

Vol 127 (2) ◽

pp. 355-366

Author(s):

M Menotti-Raymond ◽

W T Starmer ◽

D T Sullivan

Keyword(s):

Sequence Divergence ◽

Drosophila Hydei ◽

Repleta Group ◽

Drosophila Mulleri ◽

Duplication Events ◽

Independent Duplication ◽

The Difference ◽

Upstream Exon ◽

Complex Manner

Abstract Drosophila of the repleta group have a duplication of the gene which encodes alcohol dehydrogenase (ADH). We report the nucleotide sequence of an 8.4-kb region of genomic DNA of Drosophila hydei which includes the entire Adh region. Analysis of this sequence reveals similarity in organization to the Adh region of Drosophila mojavensis and Drosophila mulleri of the mulleri subgroup, with three genes ordered 5' to 3', Adh-psi, Adh-2, Adh-1. Deletion of a nucleotide in the second codon of each pseudogene suggests that the first Adh duplication occurred before the divergence of the hydei and mulleri subgroups. However, Adh-1 and Adh-2 of D. hydei are significantly more alike than Adh-1 and Adh-2 of D. mojavensis. Models to account for the difference in similarity between the coding genes were tested by orthologous and paralogous comparisons of the extent of sequence divergence. A model which proposes that independent duplication events generated Adh-1 and Adh-2 in the two lineages is supported by these data. The D. hydei pseudogene is transcribed and the transcript is processed in a complex manner. An intron of greater than 6.2 kb exists between the first "coding" exon and an upstream exon which is approximately 250 nucleotides in length.

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A Case of Fundus Oculi Albinoticus Diagnosed as Angelman Syndrome by Genetic Testing

Case Reports in Ophthalmology ◽

10.1159/000485964 ◽

2018 ◽

Vol 9 (1) ◽

pp. 108-113 ◽

Cited By ~ 1

Author(s):

Yurie Fukiyama ◽

Masahiro Tonari ◽

Junko Matsuo ◽

Hidehiro Oku ◽

Jun Sugasawa ◽

...

Keyword(s):

Genetic Testing ◽

Visual Tracking ◽

Angelman Syndrome ◽

Optic Atrophy ◽

Chromosome 15 ◽

Complete Physical Examination ◽

Respiratory Disturbance ◽

Testing Case ◽

Fundus Oculi

Purpose: To report a case of fundus oculi albinoticus diagnosed as Angelman syndrome (AS) via genetic testing. Case Report: This study reports on a 4-year-old boy. Since he had been having respiratory disturbance since birth, he underwent a complete physical examination to investigate the cause. The results indicated that he had various brain congenital abnormalities, such as a thin corpus callosum, as well as hydronephrosis, an atrial septal defect, and skin similar to patients with fundus oculi albinoticus. Examination revealed bilateral fundus oculi albinoticus, mild iridic hypopigmentation, optic atrophy, and poor visual tracking. Genetic testing revealed a deletion in the Prader-Willi syndrome/AS region on chromosome 15, and together with the results of methylation analysis, his condition was diagnosed as AS. Follow-up examinations revealed no change in the fundus oculi albinoticus and optic atrophy, nor did they indicate poor visual tracking. Conclusions: When fundus oculi albinoticus and optic atrophy are observed in patients with multiple malformations, AS should be considered as a differential diagnosis.

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