Behavioral Differences Among Subjects With Prader-Willi Syndrome and Type I or Type II Deletion and Maternal Disomy

Butler, Merlin G.; Bittel, Douglas C.; Kibiryeva, Nataliya; Talebizadeh, Zohreh; Thompson, Travis

doi:10.1542/peds.113.3.565

Cited by 258 publications

(274 citation statements)

References 30 publications

(31 reference statements)

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“…The higher number of Type 2 vs Type 1 is similar to the findings of other studies. [15][16][17] The prevalence of unique or atypical deletions was higher than what we expected and has not previously been reported for PWS, but was comparable to the prevalence rate (9.1%) found in AS. 7 The 15q11.2-q13 region is highly vulnerable to structural rearrangements, such as deletions, duplications, supernumerary marker chromosomes, and translocations due to presence of LCRs in the region.…”

Section: Discussionsupporting

confidence: 78%

“…14 Several studies have investigated phenotypic characteristics between PWS individuals with Type 1 vs Type 2 deletions, but there has been a lack of consensus among the different studies. For example, Butler et al 15 reported individuals with Type 1 deletion (n¼12) showed worse adaptive behavior, more severe compulsive behavior and more impairments in reading, math skills and visual perception than those with Type 2 deletion (n¼14). In contrast, Dykens and Roof 16 (Type 1, n¼26; Type 2, n¼29) and Milner et al 17 (Type 1, n¼14; Type 2, n¼32) did not find significant phenotypic differences between the two main deletion subtypes.…”

Section: Introductionmentioning

confidence: 99%

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Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

et al. 2011

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Prader-Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1-BP3 and BP2-BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylationspecific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n¼5) or larger (n¼2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in B8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

et al. 2011

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“…However, at this time, CMA is more expensive to have more compulsions and poorer adaptive behavior, intellectual ability, and academic achievement than those with type 2 deletions (BP2-BP3) deletions. 131,132 Two other studies found much less clinically significant differences between individuals with these two deletion types. 133,134 diAGnOstic testinG DNA methylation analysis is the most efficient way to start the genetic workup if PWS is suspected clinically (Figure 5 and Table 3).…”

Section: Paternal Deletionmentioning

confidence: 92%

Prader-Willi syndrome

Cassidy

Schwartz

Miller

et al. 2012

Genetics in Medicine

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“…In addition, NIPA1 is implicated in spastic paraplegia, 17 suggesting that it may be important for central nervous system development and/or function. Hence, we report gene-expression studies with the 4 genes located between BP1 and BP2 in those individuals with PWS with TI or TII deletions previously studied 14 and examined the relationship between messenger-RNA (mRNA) levels and behavioral-and intellectual-assessment scores.…”

Section: Introductionmentioning

confidence: 99%

Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

Bittel

Kibiryeva²,

Butler³

2006

Pediatrics

Self Cite

105

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Prader-Willi syndrome is a neurodevelopmental disorder that is characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia (leading to obesity in early childhood), learning problems, and behavioral difficulties. A paternal 15q11-q13 deletion is found in ~70% of patients with Prader-Willi syndrome, ~25% have uniparental maternal disomy 15, and the remaining 2% to 5% have imprinting defects. The proximal deletion breakpoint in the 15q11-q13 region occurs at 1 of 2 sites located within either of 2 large duplicons allowing for the identification of 2 deletion subgroups. The larger, type I (TI) deletion involves breakpoint 1, which is close to the centromere, whereas the smaller, type II (TII) deletion involves breakpoint 2, located ~500 kilobases distal to breakpoint 1. Breakpoint 3 is located at the distal end of the 15q11-q13 region and common to both typical deletion subgroups. Analyses of the genetic subtypes of Prader-Willi syndrome to date have primarily compared individuals with typical deletion and uniparental maternal disomy 15 without grouping the individuals with a deletion into TI or TII. Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters. We previously presented the first assessment of clinical differences in individuals with Prader-Willi syndrome categorized as having type I or II deletions. Adaptive behavior, obsessive-compulsive behaviors, reading, math, and visual-motor integration assessments were generally poorer in individuals with Prader-Willi syndrome and the TI deletion compared with subjects with Prader-Willi syndrome with the TII deletion or uniparental maternal disomy 15. Four genes (NIPA1, NIPA2, CYFIP1, and GCP5) have been identified in the chromosomal region between breakpoints 1 and 2 and are implicated in compulsive behavior and lower intellectual ability observed in individuals with Prader-Willi syndrome with TI versus TII deletions. We quantified messenger-RNA levels of these 4 genes in actively growing lymphoblastoid cells derived from 8 subjects with Prader-Willi syndrome with the TI deletion (4 males, 4 females; mean: age 25.2 ± 8.9 years) and 9 with the TII deletion (3 males, 6 females; mean age: 19.5 ± 5.8 years). Messenger-RNA levels were correlated with validated psychological and behavioral scales administered by trained psychologists blinded to genotype status. Messenger RNA from NIPA1, NIPA2, CYFIP1, and GCP5 was reduced but detectable in the subjects with Prader-Willi syndrome with the TI deletion, supporting biallelic expression. For the most part, Address correspondence to Merlin G. Butler, MD, PhD, Children's Mercy Hospitals and Clinics, Section of Medical Genetics and Molecular Medicine, 2401 Gillham Rd, Kansas City, MO 64108. mgbutler@cmh.edu. The authors have indicated they have no financial relationships relevant to this article to disclose. Prader-willi syndrom...

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Behavioral Differences Among Subjects With Prader-Willi Syndrome and Type I or Type II Deletion and Maternal Disomy

Cited by 258 publications

References 30 publications

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

Prader-Willi syndrome

Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

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