Analysis of the Prader‐Willi syndrome chromosome region using quantitative microsphere hybridization (QMH) array

Newkirk, Heather L.; Bittel, Douglas C.; Butler, Merlin G.

doi:10.1002/ajmg.a.32459

Cited by 12 publications

(12 citation statements)

References 27 publications

(53 reference statements)

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“…Other disorders in the future may include PWS and AS, but more research is needed. Digital PCR and quantitative microsphere hybridization (QMH) utilizing nanoparticle technology to identify copy number status are under investigation for both prenatal and postnatal diagnostic purposes and further supported by a report from Newkirk et al in identifying submicroscopic deletions of chromosome 15q11–q13 region in PWS.…”

Section: Resultsmentioning

confidence: 99%

Benefits and limitations of prenatal screening for Prader–Willi syndrome

Butler

2016

Prenatal Diagnosis

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This review the status of genetic laboratory testing in Prader-Willi syndrome (PWS) due to different genetic subtypes, most often a paternally derived 15q11-q13 deletion, with benefits and limitations related to prenatal screening. Medical literature was searched for prenatal screening and genetic laboratory testing methods in use or under development and discussed in relationship to PWS. Genetic testing includes six established laboratory diagnostic approaches for PWS with direct application to prenatal screening. Ultrasonographic, obstetric and cytogenetic reports were summarized in relationship to the cause of Prader-Willi syndrome and identification of specific genetic subtypes including maternal disomy 15. Advances in genetic technology were described for diagnosing PWS specifically DNA methylation and high-resolution chromosomal SNP microarrays as current tools for genetic screening and incorporating next generation DNA sequencing for noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Positive experiences are reported with NIPT for detection of numerical chromosomal problems (aneuploidies) but not for structural problems (microdeletions). These reports will be discussed along with future directions for genetic screening of PWS. In summary, this review describes and discusses the status of established and ongoing genetic testing options for PWS applicable in prenatal screening including NIPT and future directions for early diagnosis in Prader-Willi syndrome.

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Section: Resultsmentioning

confidence: 99%

Benefits and limitations of prenatal screening for Prader–Willi syndrome

Butler

2016

Prenatal Diagnosis

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“…The identification of small deletions in a subgroup of patients (8–15%) with an imprinting defect has led to the definition of a bipartite IC that regulates in cis imprint resetting and imprint maintenance in the whole chromosome 15q11q13 imprinted domain [Sutcliffe et al, 1994; Buiting et al, 1995]. To date, ∼21 IC‐deletions in patients with PWS and 13 IC‐deletions plus one inversion in patients with AS and an imprinting defect have been identified [Sutcliffe et al, 1994; Saitoh et al, 1996; Schuffenhauer et al, 1996; Ohta et al, 1999a,b; Bielinska et al, 2000; Buiting et al, 2000; McEntagart et al, 2000; Ming et al, 2000; El‐Maarri et al, 2001; Raca et al, 2004; Camprubi et al, 2007; Newkirk et al, 2008; Ronan et al, 2008; Buiting et al, unpublished work]. Two smallest regions of overlap (SRO) define two critical elements in the IC region, the AS‐SRO and the PWS‐SRO [Buiting et al, 1995].…”

Section: Genetic Lesionsmentioning

confidence: 99%

Prader–Willi syndrome and Angelman syndrome

Buiting

2010

American J of Med Genetics Pt C

301

238

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Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurogenetic disorders in which imprinted genes on the proximal long arm of chromosome 15 are affected. Although the SNORD116 gene cluster has become a prime candidate for PWS, it cannot be excluded that other paternally expressed genes in the chromosomal region 15q11q13 contribute to the full phenotype. AS is caused by a deficiency of the UBE3A gene, which in the brain is expressed from the maternal allele only. The most frequent genetic lesions in both disorders are a de novo deletion of the chromosomal region 15q11q13, uniparental disomy 15, an imprinting defect or, in the case of AS, a mutation of the UBE3A gene. Microdeletions in a small number of patients with PWS and AS have led to the identification of the chromosome 15 imprinting center (IC). The IC consists of two critical elements, which act in cis to regulate imprinting in the whole chromosome 15q11q13 imprinted domain.

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“…Two of our individuals (PWS1 and PWS2) were previously reported with conflicting results regarding their microdeletion status within the IC region (Mascari et al, ‐ nondeletion; Ohta et al, ‐ nondeletion; Newkirk et al, ‐ microdeletion). Our results using the newer methods of ddPCR, high‐resolution SNP microarrays, WES, and MS‐MLPA are in agreement with initial reports of these two individuals having imprinting defects caused by epimutations and not due to IC microdeletions.…”

Section: Discussionmentioning

confidence: 76%

“…A series of ddPCR assays spanning 3 kbp of the PWS IC of chromosome 15 was used to identify microdeletions from PWS individuals known to have an IC defect. In all cases, PWS IC defect status was determined by prior analysis (e.g., Mascari et al, ; Ohta et al, ; Newkirk, Bittel, & Butler, , Butler, ) but in 13 individuals the IC microdeletion status was not defined prior to the involvement in this study or was questionable (PWS1 and PWS2). The ddPCR CN for all three assays was readily distinguishable in each individual (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…It was also reported that the parents of PWS1 and PWS2 had normal SNRPN methylation patterns. Newkirk et al () examined PWS1, PWS2, and their available family members using Quantitative Microsphere Hybridization (QMH) probes specific to the PWS IC region. Quantitative Microsphere Hybridization results showed that PWS1, PWS2, their fathers, and their PGMs all had a microdeletion in the PWS IC region on chromosome 15.…”

Section: Resultsmentioning

confidence: 99%

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Analysis of the Prader–Willi syndrome imprinting center using droplet digital PCR and next‐generation whole‐exome sequencing

Hartin

Hossain

Francis

et al. 2019

Molec Gen & Gen Med

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Background Detailed analysis of imprinting center (IC) defects in individuals with Prader–Willi syndrome (PWS) is not readily available beyond chromosomal microarray (MA) analysis, and such testing is important for a more accurate diagnosis and recurrence risks. This is the first feasibility study of newly developed droplet digital polymerase chain reaction (ddPCR) examining DNA copy number differences in the PWS IC region of those with IC defects. Methods The study cohort included 17 individuals without 15q11‐q13 deletions or maternal disomy but with IC defects as determined by genotype analysis showing biparental inheritance. Seven sets of parents and two healthy, unrelated controls were also analyzed. Results Copy number differences were distinguished by comparing the number of positive droplets detected by IC probes to those from a chromosome 15 reference probe, GABRβ3. The ddPCR findings were compared to results from other methods including MA, and whole‐exome sequencing (WES) with 100% concordance. The study also estimated the frequency of IC microdeletions and identified gene variants by WES that may impact phenotypes including CPT2 and NTRK1 genes. Conclusion Droplet digital polymerase chain reaction is a cost‐effective method that can be used to confirm the presence of microdeletions in PWS with impact on genetic counseling and recurrence risks for families.

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Analysis of the Prader‐Willi syndrome chromosome region using quantitative microsphere hybridization (QMH) array

Cited by 12 publications

References 27 publications

Benefits and limitations of prenatal screening for Prader–Willi syndrome

Benefits and limitations of prenatal screening for Prader–Willi syndrome

Prader–Willi syndrome and Angelman syndrome

Analysis of the Prader–Willi syndrome imprinting center using droplet digital PCR and next‐generation whole‐exome sequencing

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