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

Procter, Melinda; Chou, Lan-Szu; Tang, Wei; Jama, Mohamed; Mao, Rong

doi:10.1373/clinchem.2006.067603

Cited by 86 publications

(66 citation statements)

References 30 publications

(28 reference statements)

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“…The commercially available MS-MLPA assay by MRC-Holland (Amsterdam, The Netherlands) combines both DNA methylation analysis and dosing analysis across the PWS region and has been shown to be very effective. 139,140 The newest version as of this writing (ME028-B1) comes as a kit with 32 dosing probes specific for the 15q11.2 region and 14 probes outside the region (on chromosome 15 and other chromosomes), which serve as controls for copy number changes. In addition, five of the probes determine the DNA methylation status at differentially methylated sites in 15q11.2.…”

Section: Paternal Deletionmentioning

confidence: 99%

Prader-Willi syndrome

Cassidy

Schwartz

Miller

et al. 2012

Genetics in Medicine

1,111

1,193

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Section: Paternal Deletionmentioning

confidence: 99%

Prader-Willi syndrome

Cassidy

Schwartz

Miller

et al. 2012

Genetics in Medicine

1,111

1,193

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“…The remaining cases, which show a normal pattern of DNA methylation, are due to UBE3A point mutations or small intragenic rearrangements. UBE3A sequencing that returns normal excludes point mutations, but small deletions within UBE3A require multiplex ligationdependent probe amplification for detection [13]. While it was formerly believed that 10-15 % of cases of AS were due to an as-yet-unrecognized molecular etiology, it is more likely that these patients represent phenocopies and actually have other diagnoses, such as those listed in Table 1 [2,6].…”

Section: Genetic Etiology and Diagnosismentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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“…Further testing is required to identify the underlying molecular mechanism as outlined in Testing Strategy. Newer methods involving pyrosequencing, 117 methylation-specific multiplex ligation-dependent probe amplification, 118,119 sequence-based quantitative methylation analysis, 120 and other methods 121 of copy-number analysis may soon provide sufficient quantitation to differentiate deletions from an ID or from UPD.…”

Section: Dna Methylation Analysismentioning

confidence: 99%