Chromosome 15 Imprinting Disorders: Genetic Laboratory Methodology and Approaches

Butler, Merlin G.; Duis, Jessica

doi:10.3389/fped.2020.00154

Cited by 30 publications

(25 citation statements)

References 35 publications

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“…AS is caused by the loss or mutation of regional imprinting and maternal genes especially influences on the UBE3A gene. UBE3A is the only gene in 15q11‐q13 that shows maternal allele preference (Butler & Duis, 2020; Gu et al, 2019). Microdeletion of 15q11 causes 70% to 90% of cases, UPD causes 3% to 7% of cases, and single‐gene defects cause only 2% to 4% of cases (Neubert et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

Huang

Chen

et al. 2021

Molec Gen & Gen Med

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Background The 15q11‐q13 region contains three breakpoints (BP1 to BP3), and copy number variations often occur in the region. Aims 15q11‐q13 microdeletion and microduplication are usually associated with Prader‐Willi and Angelman syndromes, respectively. It is not yet clear to what extent microdeletion and microduplication affect the physical health of the fetus and the child. In this study, we examined seven fetuses ranging in gestational age from 15 to 27 weeks. Materials & Methods Detailed prenatal screening and laboratory examinations were performed, while karyotype analysis and chromosomal microarray analysis (CMA) of the amniotic fluid and umbilical cord blood were applied for genetic analysis. Results CMA analysis showed that four fetuses harbored a microdeletion and one fetus showed a microduplication at 15q11.2 BP1‐BP2, two fetuses had a microdeletion at 15q11‐q13 BP2‐BP3, and one fetus had an additional microdeletion at 16p13.11. Discussion There is no clear standard for the clinical diagnosis of 15q11‐q13 microdeletion and microduplication, some of them have clinical phenotypes or are clinically affected. Conclusion Therefore, parents of such fetuses should be informed of the possibility of microdeletions or microduplications to mitigate the psychological burden, and medical consultation and assistance should be provided when communicating the results of the mid‐gestation screening.

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Section: Discussionmentioning

confidence: 99%

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

Huang

Chen

et al. 2021

Molec Gen & Gen Med

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“…These typical deletions are seen in both PWS and AS. Also, atypical 15q11-q13 deletions that are larger or smaller than the typical deletions are seen in about 7% of patients with PWS or AS as a cause ( Beygo et al, 2019 ; Butler et al, 2019a ; Butler and Duis, 2020 ) and would be identified with this streamlined approach for molecular diagnostics. The results were compared with the MLPA copy number assessment for orthogonal confirmation.…”

Section: Methodsmentioning

confidence: 99%

“…not from non-deletion maternal heterodisomy 15 status (Butler et al, 2019a;Butler and Duis, 2020). The streamlined molecular diagnostic approach we describe will identify microdeletions as well as point mutations in the imprinting center and therefore should eliminate the need for additional testing using genotyped chromosome 15 markers with parental DNA.…”

Section: Head-to-head Analysismentioning

confidence: 99%

“…As reviewed previously, testing for Prader–Willi and Angelman syndromes (PWS/AS) has historically required a stepwise approach taking up valuable time and resources (e.g., Velinov et al, 2000 ; Martínez et al, 2006 ; Ramsden et al, 2010 ; Poole et al, 2013 ; Beygo et al, 2019 ; Butler et al, 2019a ; Butler and Duis, 2020 ). By applying multiple analytical methodologies to whole-exome sequencing (WES) data ( Hartin et al, 2019 ) for the identification of copy number changes and combined with methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) (e.g., Henkhaus et al, 2012 ), one can deduce both the diagnostic status and most likely molecular mechanism in a single clinical report.…”

Section: Introductionmentioning

confidence: 99%

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

Strom¹,

Hossain

Grigorian³

et al. 2021

Front. Genet.

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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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“…PWS is recognized as the first example of errors in genomic imprinting and accounts for about 1 in 15,000 live births with more than 400,000 individuals worldwide. [1][2][3][4][5][6] Background Certain abnormal neurodevelopmental behavioral features in PWS specifically skin picking are more common than in other syndromes with intellectual disability. Skin picking is found in 81% of individuals with PWS at an average age of 18 years with 40% of all self-injurious behavior occurring on the legs (41%), particularly the front, 42% on the head including…”

Section: Introductionmentioning

confidence: 99%

Prolapsed Rectum and Risk Factors in Prader–Willi Syndrome: A Case-Based Review

Butler

2021

J Pediatr Genet

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A 14-year-old boy with Prader–Willi syndrome (PWS) with maternal disomy 15 is reported with rectal prolapse as only the second patient in the literature. With predisposing risk factors present for rectal damage and prolapse in this syndrome, the incidence must be higher and therefore underreported. These risk factors include skin and rectal picking, self-stimulation, altered pain sensation, decreased muscle mass, strength and physical activity with hypotonia, and gastrointestinal (GI) disturbances. Pertinent literature was reviewed and analyzed that focused on clinical features and behavior seen in PWS as underrecognized risk factors for developing rectal damage and prolapse. An illustrative case is presented as the second patient reported with PWS and a prolapsed rectum. A discussion of predisposing behavioral and clinical risk factors is presented including for self-stimulation, rectal picking, chronic constipation, decreased gut motility, reduced water intake, and a restricted diet. Although a paucity of cases do exist, physical, behavioral, and GI findings common in PWS may contribute to rectal prolapse requiring better awareness and proactive surveillance, management, and treatment protocols for patients affected with this rare obesity-related genetic disorder.

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Chromosome 15 Imprinting Disorders: Genetic Laboratory Methodology and Approaches

Cited by 30 publications

References 35 publications

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

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

Prolapsed Rectum and Risk Factors in Prader–Willi Syndrome: A Case-Based Review

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