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Cited by 243Genomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental DisordersGenome Rearrangement Algorithms

The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review

Open access
Cox, Devin, Butler, Merlin·2015·International Journal of Molecular Sciences
DOI 10.3390/ijms16024068PMC PMC4346944
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Abstract

Patients with the 15q11.2 BP1–BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%–1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1–BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity.

AI snapshot

Written from the paper’s full text.

TL;DR

The 15q11.2 BP1–BP2 microdeletion (Burnside-Butler syndrome) is a recognized susceptibility locus involving four non-imprinted genes and associated with developmental, speech, behavioral, psychiatric, and mild dysmorphic features with incomplete penetrance and variable expressivity. This review summarizes clinical features from about 200 reported individuals and estimates prevalence at 0.57%–1.27% among patients presenting for microarray analysis.

Key findings

  • The microdeletion involves four genes—TUBGCP5, CYFIP1, NIPA1, and NIPA2—and prevalence ranges from 0.57%–1.27% of patients presenting for microarray analysis, a two- to four-fold increase compared with controls; about 0.25% of control cohorts (n = 66,462) carried the deletion.
  • Common features from about 200 individuals included developmental delay (73%), speech delay (67%), dysmorphic ears (46%), palatal anomalies (46%), writing difficulties (60%), reading difficulties (57%), memory problems (60%), verbal IQ ≤75 (50%), general behavioral problems unspecified (55%), and abnormal brain imaging (43%).
  • Less common features included seizures/epilepsy (26%), autism spectrum disorder (27%), ADD/ADHD (35%), schizophrenia/paranoid psychosis (20%), and motor delay (42%).
  • Penetrance was estimated at 10.4%, with incomplete penetrance and variable expressivity; among individuals with parental data, 22/43 (51%) inherited the deletion from an apparently healthy parent and 10/29 (35%) from an abnormal parent, while reported de novo frequency ranged from 5%–22%.

Methods

  • Literature review of published reports on individuals with the 15q11.2 BP1–BP2 microdeletion, summarizing clinical features from about 200 individuals.
  • Features were grouped into five categories: growth and development, dysmorphic features, intelligence and academic achievement, behavioral and psychiatric problems, and other related medical concerns.
  • Main analysis was descriptive aggregation of frequencies and percentages across studies, presented in Tables 1–5; no new primary data were generated.

Limitations

  • The paper states that not all individuals with the deletion are clinically affected, and the region shows incomplete penetrance and variable expressivity; penetrance estimates may be limited by paucity of inheritance data.
  • The paper states that phenotypic information was unavailable or incomplete for all parents found to carry the deletion, and that further DNA sequencing of the non-deleted allele, studies of modifying genes, and neuropsychiatric testing of family members are needed.
  • The paper notes that very few individuals were reported for some intelligence/academic findings, so further studies are needed; evident from the tables, several features have very small denominators (e.g., verbal IQ ≤75, 2/4; performance IQ ≤75, 1/3; reading difficulties, 4/7; writing difficulties, 3/5; memory problems, 3/5), and the review relies on heterogeneous published cohorts without standardized phenotyping.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms16024068

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

34 of 60 cited sources checked · 18 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Individuals with the larger typical 15q11-q13 type I deletion in Prader-Willi and Angelman syndromes have more severe neurodevelopmental symptoms than those with the smaller typical type II deletion.

    “Several studies have shown that individuals with the larger typical 15q11–q13 type I deletion which is found in both Prader-Willi and Angelman syndromes are reported to have more severe neurodevelopmental symptoms as compared to those individuals with the smaller typical type II deletion [5,6,7,8,9,10].”
    Quote in the paperNot a substantial claim3 of 6 sources checked
    • cites [5] Butler, 2004, Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy, Pediatrics source

      The Abstract reports that type I deletions are larger than type II deletions and that people with Prader-Willi syndrome and type I deletions generally had more behavioral and psychological problems. The study did not compare deletion types in Angelman syndrome, and the Discussion cautions that most measured characteristics did not differ significantly between deletion groups. It therefore supports the Prader-Willi portion, not the claim across both syndromes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [6] Bittel, 2006, Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome, Pediatrics source

      The Abstract reports that people with Prader-Willi syndrome and the larger type I deletion generally had poorer behavioral and academic outcomes than those with the smaller type II deletion. The cited paper does not report the corresponding symptom comparison for Angelman syndrome, so it supports only the Prader-Willi portion of the claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [7] Hartley, 2005, Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome, Am. J. Med. Genet. A source
    • cites [8] Milner, 2005, Prader-Willi syndrome: Intellectual abilities and behavioural features by genetic subtype, J. Child Psychol. Psychiatry source
    • cites [9] Sahoo, 2007, Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: Molecular characterization and genotype-phenotype correlations, Eur. J. Hum. Genet. source

      The Introduction and Discussion report that children with Angelman syndrome and larger class I deletions had greater cognitive and behavioral impairment than those with class II deletions. The paper identifies these as common AS/PWS deletion types, but the cited comparison of neurodevelopmental symptoms concerns Angelman syndrome; it does not establish the same comparison for Prader-Willi syndrome. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [10] Varela, 2005, Impact of molecular mechanisms, including deletion size, on Prader-Willi syndrome phenotype: Study of 75 patients, Clin. Genet. source
  • Premisecitation

    The NIPA2 gene accounted for the largest number of significant correlations between mRNA levels and phenotypic features.

    “The NIPA2 gene accounted for the largest number of significant correlations between the mRNA levels and phenotypic features.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Bittel, 2006, Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome, Pediatrics source
  • Premisecitation

    The 15q11.2 BP1-BP2 microdeletion involves four genes: TUBGCP5, CYFIP1, NIPA1, and NIPA2.

    “The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Chai, 2003, Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons, Am. J. Hum. Genet. source
  • Premisecitation

    The penetrance of the 15q11.2 BP1-BP2 microdeletion has been estimated at 10.4%.

    “The penetrance of the 15q11.2 BP1–BP2 microdeletion has also been estimated at 10.4% [28] or an approximate two fold increase over the general population risk but may be due to paucity of inheritance data.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Rosenfeld, 2013, Estimates of penetrance for recurrent pathogenic copy-number variants, Genet Med. source
  • Premisecitation

    Chaste et al. found a greater effect on the autism phenotype in males.

    “Chaste et al. [32] found a small risk regarding this microdeletion and autism but a greater effect on the autism phenotype in males and when maternally inherited.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Chaste, 2014, Modest impact on risk for Autism Spectrum Disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2, Autism Res. source

      The Discussion says SRS analyses suggested that males might be more sensitive to the CNV, with a greater effect in fathers than mothers. This was a tentative finding about autism-related social responsiveness in relatives, not an established greater effect on the autism phenotype generally; the same section reports no effect on phenotype severity in probands. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Premisecitation

    PWS individuals with type I deletions showed more compulsive and self-injurious behaviors and visual perception impairment along with lower intelligence, reading and math scores than those with type II deletions.

    “PWS individuals with type I deletions showed more compulsive and self-injurious behaviors and visual perception impairment along with lower intelligence, reading and math scores than in those with type II deletions.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Butler, 2004, Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy, Pediatrics source

      The Discussion (page unavailable) reports more compulsive behavior and poorer visual perception with type I than type II deletions. The Results and Abstract also support poorer reading and math performance and lower intellectual ability. But the Discussion explicitly says those with type I deletions did not display more self-injury than those with type II deletions. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Individuals have been reported with the 15q11.2 BP1-BP2 microdeletion and additional non-neurological clinical findings including congenital cataracts, proximal esophageal atresia and distal tracheoesophageal fistula (type C), and congenital arthrogryposis.

    “Recently, individuals have been reported with the 15q11.2 BP1–BP2 microdeletion and additional non-neurological clinical findings. These findings included congenital cataracts [14,35], proximal esophageal atresia and distal tracheoesophageal fistula (type C) [35] and congenital arthrogryposis [36].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [14] Jerkovich, 2014, Further phenotypic expansion of 15q11.2 BP1–BP2 microdeletion (Burnside-Butler) syndrome, J. Pediatr. Genet. source
    • cites [35] Wong, D., Johnson, S.M., Young, D., Iwamoto, L., Sood, S., and Slavin, T.P. (2013). Expanding the BP1–BP2 15q11.2 microdeletion phenotype: Tracheoesophageal fistula and congenital cataracts. Case Rep. Genet., 2003. source
    • cites [36] Usrey, K.M., Williams, C.A., Dasouki, M., Fairbrother, L.C., and Butler, M.G. (2014). Congenital arthrogryposis: An extension of the 15q11.2 BP1–BP2 microdeletion syndrome?. Case Rep. Genet., 2004. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Individuals with Angelman syndrome and the 15q11-q13 type I deletion had significantly more behavioral and cognitive impairments with lower expressive and total language abilities and a higher likelihood of features for autism spectrum disorder.

    “Sahoo et al. [9] reported that in individuals with Angelman syndrome and the 15q11–q13 type I deletion had significantly more behavioral and cognitive impairments with lower expressive and total language abilities and a higher likelihood of features for autism spectrum disorder.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Sahoo, 2007, Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: Molecular characterization and genotype-phenotype correlations, Eur. J. Hum. Genet. source

  • May combine two claims.

    Premisecitation

    Rees et al. found a significant association between the 15q11.2 BP1-BP2 microdeletion and schizophrenia, with a frequency of 0.64 (44/6882) among individuals having schizophrenia and the microdeletion in their study.

    “Rees et al. [40] found a significant association between the microdeletion and schizophrenia with the frequency of individuals having schizophrenia and the microdeletion from their study was 0.64 (44/6882).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Rees, 2014, Analysis of copy number variations at 15 schizophrenia-associated loci, Br. J. Psychiatry source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The four genes in the BP1-BP2 region are highly conserved and biallelically expressed.

    “Chai et al. [19] showed that these four genes are highly conserved and biallelically expressed.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Chai, 2003, Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons, Am. J. Hum. Genet. source

  • May combine two claims.

    Premisecitation

    A deletion involving the 15q11.2 BP1-BP2 region correlates with language or motor delays, behavioral problems, autism, seizures and occasionally mild dysmorphic features.

    “Collectively, they summarized that a deletion involving this genomic region correlated with language or motor delays, behavioral problems, autism, seizures and occasionally mild dysmorphic features.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Burnside, 2011, Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: A susceptibility region for neurological dysfunction including developmental and language delay, Hum. Genet. source

  • May combine two claims.

    Premisecitation

    Burnside et al. found 69 subjects with the 15q11.2 microdeletion and 77 subjects with a microduplication of the same region.

    “Specifically, 69 subjects were found with the 15q11.2 microdeletion and 77 subjects were found with a microduplication of the same region.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Burnside, 2011, Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: A susceptibility region for neurological dysfunction including developmental and language delay, Hum. Genet. source

  • May combine two claims.

    Interpretationcitation

    Low penetrance estimates may relate to subclinical manifestations of neuropsychiatric or behavioral problems or incomplete information about the parents of individuals with the 15q11.2 BP1-BP2 microdeletion or members of control cohorts.

    “Low penetrance estimates may relate to subclinical manifestations of neuropsychiatric/behavioral problems or incomplete information about the parents of individuals with 15q11.2 BP1–BP2 microdeletion or members of control cohorts [44].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [44] Girirajan, 2010, A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay, Nat. Genet. source

      The Discussion (page unavailable) says subtle features of the 16p12.1 microdeletion may lead to under-ascertainment, and it reports neuropsychiatric features in carrier parents. It does not establish this explanation for low penetrance estimates of the distinct 15q11.2 BP1–BP2 microdeletion or attribute those estimates to incomplete information about parents or control cohorts. (LLM, conf=0.79)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NIPA1 is associated with autosomal dominant hereditary spastic paraplegia.

    “NIPA1 or non-imprinted in Prader-Willi/Angelman syndrome 1 gene is the best studied gene within this region and associated with autosomal dominant hereditary spastic paraplegia [20,21].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [20] Chen, 2005, Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families, Hum. Mutat. source
    • cites [21] Rainier, 2003, NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6), Am. J. Hum. Genet. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Burnside et al. found that 0.86% of approximately 17,000 individuals had an abnormality (deletion or duplication) of the 15q11.2 BP1-BP2 region.

    “They found that 0.86% of the approximate 17,000 individuals had an abnormality (deletion or duplication) of the 15q11.2 BP1–BP2 region.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Burnside, 2011, Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: A susceptibility region for neurological dysfunction including developmental and language delay, Hum. Genet. source

  • May combine two claims.

    Premisecitation

    The penetrance for the 15q11.2 microdeletion is low compared to the 16p11.2 deletion with a penetrance estimated at 62.4%.

    “The penetrance for the 15q11.2 microdeletion is low compared to other microdeletion syndromes such as the 16p11.2 deletion with a penetrance estimated at 62.4% [28].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Rosenfeld, 2013, Estimates of penetrance for recurrent pathogenic copy-number variants, Genet Med. source

      The Results report 10.4% penetrance for 15q11.2 deletions versus 62.4% for *distal* 16p11.2 deletions. The cited sentence omits “distal,” making the 62.4% estimate sound applicable to 16p11.2 deletions generally; the paper also distinguishes proximal deletions. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen in patients with the 15q11.2 BP1-BP2 microdeletion.

    “Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems.

    “Patients with the 15q11.2 BP1–BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    In the literature review, 4% of individuals with the 15q11.2 BP1-BP2 microdeletion had cataracts.

    “Occasional features seen within the literature regarding medical conditions included congenital heart defect (9%), genital abnormalities (7%), recurrent infections (7%), cataracts (4%), hearing loss or impairment (4%), tracheoesophageal fistula (2%), and omphalocele (2%).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

  • May combine two claims.

    Findingreasoning

    Not all individuals with defects within the 15q11.2 band share a clinical phenotype or are clinically affected.

    “Not all individuals with defects within the 15q11.2 band (i.e., microdeletions or microduplications) share a clinical phenotype or are clinically affected.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    In the literature review, 12% of reported individuals with the 15q11.2 BP1-BP2 microdeletion had an unusually happy expression.

    “Occasionally, reported behavioral features within the literature included an unusually happy expression (12%) and anxiety (6%) [16,34].”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the literature review, 2% of individuals with the 15q11.2 BP1-BP2 microdeletion had omphalocele.

    “Occasional features seen within the literature regarding medical conditions included congenital heart defect (9%), genital abnormalities (7%), recurrent infections (7%), cataracts (4%), hearing loss or impairment (4%), tracheoesophageal fistula (2%), and omphalocele (2%).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

  • May combine two claims.

    Findingnone given

    The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome is a recognized condition, with over 200 individuals identified from the literature using chromosomal microarray analysis.

    “The 15q11.2 BP1–BP2 microdeletion (Burnside-Butler) syndrome is now a recognized condition with over 200 individuals identified from the literature using chromosomal microarray analysis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the literature review, 2% of individuals with the 15q11.2 BP1-BP2 microdeletion had tracheoesophageal fistula.

    “Occasional features seen within the literature regarding medical conditions included congenital heart defect (9%), genital abnormalities (7%), recurrent infections (7%), cataracts (4%), hearing loss or impairment (4%), tracheoesophageal fistula (2%), and omphalocele (2%).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the literature review, 4% of individuals with the 15q11.2 BP1-BP2 microdeletion had hearing loss or impairment.

    “Occasional features seen within the literature regarding medical conditions included congenital heart defect (9%), genital abnormalities (7%), recurrent infections (7%), cataracts (4%), hearing loss or impairment (4%), tracheoesophageal fistula (2%), and omphalocele (2%).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    There has been no case to date where haploinsufficiency of NIPA1 due to a deletion has led to hereditary spastic paraplegia.

    “There has been no case to date where haploinsufficiency of NIPA1 due to a deletion has led to hereditary spastic paraplegia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the literature review, 7% of individuals with the 15q11.2 BP1-BP2 microdeletion had recurrent infections.

    “Occasional features seen within the literature regarding medical conditions included congenital heart defect (9%), genital abnormalities (7%), recurrent infections (7%), cataracts (4%), hearing loss or impairment (4%), tracheoesophageal fistula (2%), and omphalocele (2%).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Individuals with PWS having 15q11-q13 type I deletions acquired speech later than those with type II deletions.

    “Varela et al. [10] found that individuals with PWS having 15q11–q13 type I deletions acquired speech later than those with type II deletions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Varela, 2005, Impact of molecular mechanisms, including deletion size, on Prader-Willi syndrome phenotype: Study of 75 patients, Clin. Genet. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Individuals with PWS having type I deletions had significantly higher Reiss maladaptive behavior scores for depression than individuals with type II deletions.

    “Hartley et al. [7] also found that individuals with PWS having type I deletions had significantly higher Reiss maladaptive behavior scores for depression (physical signs) than individuals with type II deletions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Hartley, 2005, Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome, Am. J. Med. Genet. A source

  • May combine two claims.

    Interpretationnone given

    The clinical features of the 15q11.2 BP1-BP2 microdeletion syndrome show incomplete penetrance and variable expressivity.

    “Clinically, neurological dysfunction, developmental and language delay are the most commonly associated findings followed by motor delay, ADD/ADHD and autism spectrum disorder showing incomplete penetrance and variable expressivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Individuals with Angelman syndrome and the 15q11-q13 type I deletion had more severe seizures and were refractory to treatment compared with those having the type II deletion.

    “Valente et al. [11] also reported in Angelman syndrome that those with the 15q11–q13 type I deletion had more severe seizures and were refractory to treatment compared with those having the type II deletion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Valente, 2013, Angelman syndrome caused by deletion: A genotype-phenotype correlation determined by breakpoint, Epilepsy Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    87.5% of patients with the 15q11.2 BP1-BP2 deletion in Abdelmoity et al. had developmental delay or intellectual disability.

    “They found that 87.5% of the patients with the deletion had developmental delay or intellectual disability.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Abdelmoity, 2012, 15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features, J. Dev. Behav. Pediatr. source

  • May combine two claims.

    Interpretationreasoning

    The 15q11.2 BP1-BP2 region contains genetic material showing incomplete penetrance or low penetrance of pathogenicity along with variable expressivity.

    “Therefore, this region contains genetic material showing incomplete penetrance or low penetrance of pathogenicity along with variable expressivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cafferkey et al. found 83 (0.57%) of 14,605 patients referred for genetic testing had the 15q11.2 BP1-BP2 microdeletion.

    “More recently, Cafferkey et al. [18] presented data from 14,605 patients (primarily pediatric) referred for genetic testing using microarray analysis and found 83 (0.57%) with the 15q11.2 BP1–BP2 microdeletion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Cafferkey, 2013, Phenotypic features in patients with 15q11.2 (BP1–BP2) deletion: Further delineation of an emerging syndrome, Am. J. Med. Genet. Part A source

  • May combine two claims.

    Premisecitation

    Stefansson et al. found a modest effect on verbal IQ (effect = 0.38, p = 0.033) and performance IQ (effect = 0.43, p = 0.018) from the 15q11.2 deletion.

    “Stefansson et al. [38] found a modest effect on verbal IQ (effect = 0.38, p = 0.033) and performance IQ (effect = 0.43, p = 0.018) from the 15q11.2 deletion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Stefansson, 2014, CNVs conferring risk of autism or schizophrenia affect cognition in controls, Nature source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Abdelmoity et al. found that 21% or 1.27% of 1654 consecutive pediatric patients with neurological disorders carried a 15q11.2 BP1-BP2 deletion.

    “Later, Abdelmoity et al. [17] reported a cohort of 1654 consecutive pediatric patients presenting with a range of neurological disorders and found that 21% or 1.27% of the patients carried a 15q11.2 BP1–BP2 deletion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Abdelmoity, 2012, 15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features, J. Dev. Behav. Pediatr. source
31 of 31

  • The paper relies on this without support.

    The clinical features reported in the literature for individuals with the 15q11.2 BP1–BP2 microdeletion are attributable to the deletion rather than to other genetic or environmental factors.

    “Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms.”

  • The paper relies on this without support.

    The individuals in the reviewed studies are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

    “Review of clinical features from about 200 individuals were grouped into five categories”

  • The paper relies on this without support.

    The control cohorts used to estimate prevalence are comparable to the patient cohorts.

    “which is a two to four fold increase compared with controls.”

  • The authors state this as an assumption.

    The four genes in the BP1–BP2 region are the relevant genes for the neurobehavioral phenotype.

    “the collection of findings appear to share biological pathways and presumed genetic mechanisms.”

  • The paper relies on this without support.

    The literature review captures all relevant published cases.

    “A review of the literature on growth and development in individuals with 15q11.2 BP1–BP2 microdeletions”

  • The paper relies on this without support.

    The individuals reported in the reviewed literature are representative of the broader population with the 15q11.2 BP1–BP2 microdeletion.

    “From reported patient cohorts presenting for genetic services and microarray analysis, this microdeletion syndrome can now be recognized as the most common cytogenetic abnormality found in autism spectrum disorder.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Deletion of 15q11.2(BP1-BP2) leads to a two- to fourfold increase in the risk for schizophrenia, autism and intellectual disability.

    “Deletion of 15q11.2(BP1–BP2) leads to a two to fourfold increase in the risk for schizophrenia, autism and intellectual disability [1–5].”

    From Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility (2024) · cites this paper as [3]

    The Abstract reports a two- to fourfold higher prevalence of the deletion among patients presenting for microarray analysis than among controls; it does not give a two- to fourfold increase in risk for each named condition. Sections 2.3 and 2.4 discuss intellectual disability, an association with schizophrenia, and a modest autism risk, but do not assign that magnitude to those outcomes. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • More than 200 15q11.2 deletion carriers have been reported in clinical series with mild, moderate and severe neurodevelopmental symptoms as well as malformations.

    “More than 200 15q11.2 deletion carriers have been reported in clinical series with mild, moderate and severe neurodevelopmental symptoms as well as malformations leading authors to delineate a microdeletion syndrome with considerable phenotypic variability9 and incomplete penetrance.10”

    From Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice (2019) · cites this paper as [9]

    The Abstract reviews clinical features from about 200 deletion carriers, and Table 5 in §2.5 includes a series totaling 216 carriers. The Introduction and Results describe variable neurodevelopmental findings and congenital anomalies, but the review does not classify carriers as having mild, moderate, and severe neurodevelopmental symptoms. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Palatal-abnormality percentage is doubled

    Major

    The reported 9 cases among 39 individuals correspond to about 23%, not 46%. The 46% figure is also repeated in the abstract and discussion.

    Reported 46 · recomputed 23.076923

  • Patient prevalence is stated as 21% instead of 1.27%

    Major

    The stated 21 patients among 1,654 correspond to 1.27%, not 21%. The sentence gives both incompatible percentages.

    Reported 21 · recomputed 1.269649

  • Seizure counts sum to 50, not 57

    Major

    The study numerators in the seizures/epilepsy row total 50, not the reported 57. With the reported denominator of 216, that would also change the stated 26% incidence to about 23%.

    Reported 57 · recomputed 50

  • Dysmorphic-ear percentage does not match its count

    Major

    The reported 9/39 is about 23%, not 46%. Moreover, the study counts in the row add to 10 rather than 9.

    Reported 46 · recomputed 23.076923

  • Tracheoesophageal-fistula denominator does not add up

    Minor

    The non-N/A study denominators total 46, not the reported 49.

    Reported 49 · recomputed 46

  • Genital-abnormality denominator does not add up

    Minor

    The non-N/A study denominators total 43, not the reported 46.

    Reported 46 · recomputed 43

  • Recurrent-infection denominator does not add up

    Minor

    The non-N/A study denominators total 27, not the reported 30.

    Reported 30 · recomputed 27

  • Hearing-loss denominator does not add up

    Minor

    The non-N/A study denominators total 46, not the reported 49.

    Reported 49 · recomputed 46

  • Omphalocele denominator does not add up

    Minor

    The non-N/A study denominators total 46, not the reported 49.

    Reported 49 · recomputed 46

9 of 9

Cites

Flagged first, then by citations

1 of the 48 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Cox, D., & Butler, M.
Affiliations
University of Kansas Medical Center (US)
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2015-02-13
Volume
16
Issue
2
Pages
4068-4082
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms16024068
PMC
PMC4346944
OpenAlex
W2036796020
Cited by
243
References
48
Citations by year
2026: 15 · 2025: 17 · 2024: 25 · 2023: 18 · 2022: 18 · 2021: 21 · 2020: 21 · 2019: 18 · 2018: 46 · 2017: 21 · 2016: 13 · 2015: 10
FWCI
18.49
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • KU ScholarWorks (The University of Kansas) (submittedVersion, cc-by)
Funders
NICHD (HD02528)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
Keywords
CYFIP1, NIPA1, developmental delay, language delay, dysmorphic features, neuropsychiatric disorders, autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder, seizures, incomplete penetrance, variable expressivity, genomic imbalances
MeSH terms
Autism Spectrum Disorder, Attention Deficit Disorder with Hyperactivity, Chromosome Aberrations, Chromosomes, Human, Pair 15, Epilepsy, Humans, Intellectual Disability, Schizophrenia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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