ClinGen Dosage Sensitivity Curation Page

15q11.2 recurrent region (BP1-BP2) (includes NIPA1)

  • Curation Status: Complete
  • id: ISCA-37448
  • Date last evaluated: 2017-05-25
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 2
  • ClinGen Triplosensitivity Score: Triplosensitivity unlikely


Location Information

Select assembly: (NC_000015.9) ()
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
24352232 Stefansson et al (2014) recruited adults aged 18-65 years from a large genotyped control population from Iceland to evaluate whether CNVs previously reported in affected populations are associated with cognitive and psychiatric phenotypes in 47 control individuals who carry these CNVS, compared to control individuals who do not. 15q11.2 BP1-BP2 deletions were strongly associated with a history of learning difficulties (in math and reading, dyslexia and dyscalculia) but not other cognitive traits. 15q11.2 BP1-BP2 deletions were also associated with structural MRI findings in the control carriers.
21359847 Burnside et al. (2011) perform a case-only retrospective analysis of ~17,000 cases. They compare common phenotypes among individuals with deletions (or duplications) of 15q11 BP1-BP2. The most common feature of the deletion cohort was speech delay, reported for 90% of subjects over 1 year of age. Twenty of 21 individuals with follow up studies were shown to be inherited.
25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, 15q11.2 (BP1-BP2) region deletions were observed in 200/29,085 cases versus 27/19,584 controls (p=3.19E-21), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2011) PMID 21841781 and Rosenfeld et al. (2013) PMID 23258348.

Haploinsufficiency phenotype comments:

The 15q proximal region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to deletions involving recurrent breakpoint (BP) regions BP1 and BP2, located in the proximal region of 15q11.2. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Deletions of 15q11.2 between BP1-BP2 have been associated with a broad spectrum of neurologic and behavioral phenotypes, including idiopathic generalized epilepsy, schizophrenia and related psychosis (nominal association), and developmental delay with or without dysmorphic features. These deletions have also been observed in normal-random-controls (not phenotypically characterized) and in unaffected relatives. This evidence suggests reduced penetrance, and a yet unclear complex pathogenic mechanism. Although this deletion does appear to be enriched in some case versus control studies, factors including the relative high prevalence of deletions of this region in both populations, difficulty targeting and calling CNVs in this region across different platforms and CNV calling algorithms, as well as the observations of variable phenotypes and incomplete penetrance amongst 15q11.2 (BP1-BP2) deletion carriers makes the pathogenic nature of this deletion difficult to assess. This deletion appears to be a susceptibility locus for neurologic phenotypes. Therefore the current haploinsufficiency score is 2. Additional literature is summarized below: Cox and Butler (2015; PMID: 25689425) reviewed clinical findings in common across over 200 15q11.2 (BP1-BP2) deletion carrier patients reported in the literature, which 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 (55%) and abnormal brain imaging (43%). Other features included seizures/epilepsy (26%), autism spectrum disorder (27%), ADD/ADHD (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). The authors note incomplete penetrance and variable expressivity. Vanlerberghe et al (2015; PMID: 25596525) investigated the phenotypes of 52 unrelated patients with 15q11.2 (BP1-BP2) deletion identified by aCGH testing across six French Genetic laboratories, after excluding patients with known CNV, aneuploidy or known monogenic disease. Phenotypes were numerous and variable, and included: mild or moderate developmental delay (68.3%), speech impairment (85.4%), psychological issues including ADHD, ASD, or OCD (63.4%), and a novel association with congenital heart defects (17.3%). Inheritance, available for a subset (65.4%), was de novo in 18.8% and inherited in 81.2% (52.9% from a healthy parent, 29.4% from a mildly affected parent). Incomplete penetrance and variable expressivity were observed amongst deletion carriers. Hashemi et al (2015; PMID: 25946043) reported phenotypic features of 35 individuals with deletion 15q11.2 (BP1-BP2) referred for CMA testing at their institution in Toronto, which accounted for 0.76% of all referrals. A subset of patients (12/35) had additional CNVs. Clinical findings were variable, and included in the entire cohort: developmental delay (91.4%), behavioral problems including ADHD (37.1%), dysmorphic features that did not reveal any recognizable patterns (42.9%) and ASD/autistic features (20.0%); and unspecified behavioral anomalies), and epilepsy/seizures (17.1%). Congenital anomalies were observed at an overall rate of 40%; no specific pattern or type of defect emerged for phenotypes including heart defects, neurological features, and seizure semiology. The deletion was inherited in 27/32 (84.3%) cases, 5 were de novo. The authors recommend classification of this CNV as a variant of uncertain clinical significance. Cafferkey et al (2014; PMID: 24715682) reported phenotypic features of 83 individuals with deletion 15q11.2 (BP1-BP2) referred for CMA testing at their institutions in the UK, which accounted for 0.57% of all referrals and compared phenotypic frequencies to a non-deleted cohort (n=14,522). Features that were more prevalent in the deleted cohort included general developmental delay, motor delay (a novel finding in their cohort), speech delay, ASD/autistic features, behavioral problems, dysmorphic features and epilepsy/seizures. Secondary variants were observed in 26.5% of patients. Inheritance information was unavailable for patients in this cohort. The authors conclude their data support the hypothesis that 15q11.2 (BP1-BP2) deletions confer susceptibility to a range of neuropsychiatric disorders. Chaste et al (2014; PMID: 24821083) estimated the frequency and penetrance of autism spectrum disorders in subjects with 15q11.2 (BP1-BP2) deletion from a well-characterized ASD sample (n=2525 families). The deletion was observed at a rate of 0.32% in probands and was de novo (subsequently transmitted) in only one case. The frequency between ASD probands and their unaffected siblings was not statistically different (p=0.86) and was noted to be comparable to published rates in controls, and lower than in individuals with schizophrenia or developmental delay. Penetrance was estimated at 0.013 (OR=1.3, CI: 0.42-3.96), given a prevalence of 0.01 for ASD. The authors propose the possibility of ascertainment bias leading to low incidence of BP1-BP2 deletion in their cohort, by selection of (clinically assessed) families with unaffected parents, which may omit families with rare, inherited ASD risk variants. The authors recommend classification as a variant of uncertain significance: ?they do appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.? von der Lippe et al. (2011; PMID: 21187176) describe 6 additional cases with 15q11.2 deletions (1 case involves 2 brothers for a total of 7 individuals). Parental samples were available for 5 of the 6 families: 4 dels were paternally inherited and 1 was maternally inherited. The authors state that all patients had learning or behavior problems and/or developmental delay. Additional clinical history is presented in the paper. Mefford et al. (2010; PMID: 20502679) performed array CGH in 517 patients with idiopathic epilepsy. Deletions of 15q11.2 between BP1-BP2 were identified in 5 individuals (~1%). Familial segregation was determined in 3 cases; 2 were inherited from unaffected parents, and present on an affected sibling on the third individual. de Kovel et al. (2010; PMID: 19843651) analyzed 1,234 patients with idiopathic generalized epilepsies as compared to 3,022 controls. They found the 15q11 BP1-BP2 deletion significantly enriched in cases (p=4.2e-4). The deletion was inherited in all cases were parental samples were available for analysis, and were present in at least 14 unaffected and 4 affected first-degree relatives. Mefford et al. (2009; PMID: 19506092) examined over 1,000 patients with ID for CNVs in 69 loci, including 15q11. The BP1-BP2 deletion was found in 8 of 1,010 patients, but only in 3 of 2,493 published adult controls (p=0.003). Doornbos et al. (2009; PMID: 19328872) describe 9 patients with 15q11 BP1-2 deletions among a cohort of 1,576 individuals with ID/MCA. Two deletions were de novo, 3 were maternally inherited, and 4 were paternally inherited. The authors describe the common features between the 9 individuals, including behavioral problems and delayed motor and speech development. Additional clinical features are presented in the paper. Stefansson et al. (2008; PMID: 18668039) detected nominal association of 15q11.2 BP1-BP2 with schizophrenia and related psychosis comparing a large cohort of 1,433 of patients and 33,250 controls (OR: 3.90; CI 95% 1.42-9.37 ; P= 0.007 not corrected for multiple test). Significant association was found in a replication cohort of 3,285 cases and 7,951 (OR: 14.83; P= 6.0e-4, not corrected), however, this association was not significant when patients without a defined diagnosis of schizophrenia (unspecified psychosis, schizophreniform, schizoaffective, and delusional disorders) were removed from the case cohort (OR: 2.66; P= 9.57 e-4 - uncorrected for multiple test).

  • Triplosensitivity score: Triplosensitivity unlikely
  • Strength of Evidence (disclaimer): Triplosensitivity unlikely

Triplosensitivity phenotype comment:

The 15q proximal region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to duplications involving recurrent breakpoint (BP) regions BP1 and BP2, located in the proximal region of 15q11.2. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Both evidence refuting and very limited evidence in support of a clinical association of 15q11.2 (BP1-BP2) region duplication exist in the current literature. Duplications of this region are common and the majority of studies have observed a lack of enrichment of 15q11.2 (BP1-BP2) duplications in the clinical population. Therefore, the triplosensitivity score for this region is dosage sensitivity unlikely. Relevant references are discussed below: Stefansson et al. (2014; PMID 24352232) recruited adults aged 18-65 years from a large genotyped control population from Iceland to evaluate whether CNVs previously reported in affected populations are associated with cognitive and psychiatric phenotypes. "In 136 controls carrying the reciprocal 15q11.2 (BP1-BP2) duplication the results are comparable to those of population controls on the neurocognitive tests (Supplementary Table 4a), and their GAF (0.01 s.d., P50.95), ARHQ (20.22 s.d., P50.057) and AMHQ (0.07 s.d., P50.52) scores are also in keeping with those of population controls." And, "Importantly, for both grey and white matter, 15q11.2 (BP1-BP2) duplication carriers always show reciprocal changes in exactly the same regions altered in deletion carriers, providing the first demonstration of allele-dose-dependent effects of CNVs on the structure of the human brain." Given the reported lack of associated cognitive affects, the significance of this latter phenotype is uncertain. Coe et al. (2014; PMID 25217958): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, 15q11.2 (BP1-BP2) region duplications were observed in 128/29,085 cases versus 60/19,584 controls (p=0.0112; LR: 1.44; CI 1.09 to 1.9), reaching nominal statistical significance. In a previous study by this group, Cooper et al. (2011) PMID 21841781 showed duplications of this region are not enriched in the clinical population (64/15,767 cases vs 36/8,329 controls; p=0.66; penetrance=0.05; OR: 0.931). Chaste et al. (2014; PMID: 24821083) estimated the frequency and penetrance of autism spectrum disorders in subjects with 15q11.2 (BP1-BP2) duplication from a well-characterized ASD sample (n=2525 families). The duplication was observed at a rate of 0.79% in probands and was inherited in all cases. The frequency between ASD probands and their unaffected siblings was not statistically different (p=0.19) but was noted to be higher than previously published rates in both cases and controls. Penetrance was estimated at 0.013 (OR=1.8, CI: 0.82-3.97), given a prevalence of 0.01 for ASD. The authors propose the possibility of ascertainment bias leading to low incidence of BP1-BP2 duplication in their cohort, by selection of (clinically assessed) families with unaffected parents, which may omit families with rare, inherited ASD risk variants. The authors recommend classification as a variant of uncertain significance: ?they do appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.? Burnside et al. (2011; PMID 21359847) performed a case-only retrospective analysis of ~17,000 cases. They compared common phenotypes among individuals with deletions or duplications of 15q11.2 BP1-BP2. Twenty-one of 23 subjects for whom follow up studies were performed showed the duplication was inherited. van der Zwaag et al. (2010; PMID 20029941) performed a case-control analysis of 849 patients with ASD compared to 945 controls. For 15q11.2 BP1-BP2, they found 8 duplications in cases and 4 duplications in controls (p=0.247).