ClinGen Dosage Sensitivity Curation Page

2q13 recurrent region (includes BCL2L11)

  • Curation Status: Complete
  • id: ISCA-37496
  • Date last evaluated: 2018-06-22
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 2
  • ClinGen Triplosensitivity Score: 2


Location Information

Select assembly: (NC_000002.11) ()
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
26227573 Riley et al. (2015) report three unrelated individuals (subjects 9-11) with overlapping 2q13 deletions ranging in size from 1.62 to 1.71-Mb. Two deletions (Subjects 9 and 10) overlap completely with the recurrent 2q13 region, while another deletion (Subject 11) partially overlaps this region, but is shifted distally (telomeric) to the recurrent region. Deletions of Subjects 9 and 10 were paternally inherited (no phenotypic information was available) and the deletion of Subject 11 was de novo. The authors provide a review of the literature (9 previous cases, 12 cases total). Clinical findings in common across patients include: developmental delay/intellectual disability (4/7), autism (2/4), speech delay (3/8), hypotonia (7/12), dysmorphic features (10/12), congenital heart defects (7/12), and abnormal head size (9/12).
26236398 Hladilkova et al. (2015) describe two unrelated individuals (Patients 1 and 2) with deletions involving the recurrent 2q13 (BCL2L11) region. Clinical features in common included developmental delay and mild dysmorphic facial features. Familial testing demonstrated that the mother and maternal grandmother were unaffected carriers of the deletion in one individual (Patient 1). Parental testing for patient 2 was not performed. Reduced penetrance and variable expression were emphasized. The authors also provided a review of genetic, clinical and inheritance data amongst patients with 2q13 deletions reported in the literature (29 cases total, including 13 patients from a large-scale case-control comparison study, Cooper et al., 2011). Extent of clinical characterization varies across these studies, however clinical findings in common across patients (#) include: developmental delay/intellectual disability (13), dysmorphic features (13), congenital heart defects (7), hypotonia (7), seizures (5), ASDs (4), macrocephaly (4), microcephaly (3), microphallus in males (3), and ADHD/ADD (3). Inheritance studies: 2 de novo cases, 11 cases inherited from a healthy parent, 2 cases inherited from an affected parent, and 14 with unknown inheritance.
21255006 Yu et al. (2012) describe four unrelated individuals (cases 1-4) with deletions of the recurrent 2q13 (BCL2L11) region. Clinical features of these individuals included developmental delay and non-specific dysmorphic features. Parental studies were performed for cases 1, 3, and 4 (not case 2) and indicated familial inheritance for all three cases. Cases 3 and 4 had a family history of developmental delay, suggesting co-segregation, while no information was provided for case 1. The authors review genetic, clinical and inheritance data for these newly reported cases, as well as eight others characterized by genomic microarray (12 cases total), including five cases (6-10) from the DECHIPER database and three cases previously reported by Rudd et al. (2009, cases 11-13), and one case reported by Bisgaard et al (2007, case 14). The majority of individuals with this deletion had developmental delay (93%) and non-specific facial dysmorphisms (63%). Of note, the DECIPHER cases had little to no clinical information, and four of these patients had additional CNVs. The authors also compare the frequency of 2q13 microdeletion in their patient population (4/5523 individuals referred for clinical diagnostic aCGH testing) to a control population (0/7000 presumably unaffected individuals in the DGV, accessed Aug 2010-includes 2026 the CHOP CNV database), and show significant enrichment (p=0.04, chi-square with Yates? corr.). The authors propose this microdeletion is ?probably clinically relevant?. The authors suggest additional CNVs may modify the phenotype and/or overall penetrance.

Haploinsufficiency phenotype comments:

At least 17 unrelated patients with 2q13 deletions* have been reported in the literature. Amongst affected carriers, clinical findings are variable, including DD/ID, non-specific dysmorphic features, abnormal head size (macro or microcephaly), congenital heart defects and additional nonspecific phenotypes. In the majority of cases where parental inheritance has been tested, 2q13 deletions have been found to be inherited, often from a clinically unaffected parent. Statistical enrichment has been observed from case-control comparison (reviewed below). Due to phenotypic variability and inheritance information, the current haploinsufficiency score is 2. *The proximal 2q 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 breakpoints within the 2q13 region (BCL2L11 included). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional relevant literature is summarized below: Case-control studies PMID : 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, deletions of the recurrent 2q13 (BCL2L11) region were observed in 20/29,085 cases versus 3/19,584 controls (p=0.00483; LR=4.49, CI: 1.53-15.5), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2011), PMID 21841781. Additional cases PMID: 17531565 Bisgard et al (2007) reported two brothers with the 2q13 deletion, inherited from their mother, studied by arrayCGH. Both siblings had a perinatal history of asphyxia, requiring caesarean section delivery. The brothers had developmental delays and similar mild facial dysmorphisms. Because their carrier mother was unaffected, the authors concluded this to be a normal variant. PMID: 19443486 Rudd et al. (2009) analyzed array CGH data of 2419 individuals in an effort to identify new syndrome-associated segmental duplication-mediated chromosome rearrangements. This study described three individuals (Patients 5-7, Table 1) with deletions of the recurrent 2q13 (BCL2L11) region. These individuals had clinical features that were nonspecific; although dental anomalies were observed in one individual. One deletion was paternally inherited (Patient 6), while the inheritance was unknown for the other two. The deletion was not identified in an unpublished control population, which included 347 unaffected parents of schizophrenia probands and 529 Ashkenazi Jewish patients with Crohn?s disease, dystonia or Parkinson?s disease (n=876).

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
26227573 Riley et al. (2015) report clinical findings for a second individual (Subject 12) from a family (Family 3) with a duplication of the recurrent 2q13 (BCL2L11) region-the first individual (Patient 4) was reported by Rudd et al (2009). Clinical findings of Subject 12 included dysmorphic features, developmental delay, and microcephaly. The duplication was maternally inherited and the mother was reported to have some mild learning difficulties and developmental delays. The authors review clinical findings, genetic and inheritance data for other patients reported in the literature (Table IV), which includes two additional unrelated cases (three cases total): two unrelated individuals reported by Rudd et al. (2009) (Patient 3 and Patient 4 from Family 3) and one case by Yu et al. (2012) (Case 5). Clinical findings in common across patients include DD/ID (4/4), ASD (2/4), hypotonia (2/3), dysmorphic features (3/4), and cranial phenotypes (3/3). In Family 3, the duplications were inherited, at least one parent was mildly affected; Patient 3?s duplication was paternally inherited (no clinical info available) and in Case 5 inheritance was unknown. The authors also summarize previous literature including patients from a large-scale case-control comparison study, Cooper et al., 2011, three of which inherited their duplications. The authors suggest 2q13 duplications are pathogenic with variable expressivity.
24807792 Costain et al. (2014) describe clinical findings of six adults from two unrelated families (2 cases) with a duplication of the recurrent 2q13 (BCL2L11) region. The probands (A and B) were previously identified among a large cohort of adult patients with schizophrenia (see Costain et al., 2013; PMID: 23813976). The duplication of Proband A was maternally inherited (mother also affected with other psychiatric illness), and co-segregated with psychotic disorder/psychiatric illness in a total of 5/6 affected individuals across two generations (a maternal aunt of Proband A had a different recurrent duplication involving the 16p13.11 (NDE1) region). An additional rare CNV (486.7 kb deletion in 9p24 including JAK2 and SLC1Aa) was detected in the proband and his sibling, and was inferred to be paternally inherited. In the other family (Family B), the proband was the only affected individual-parental testing was not performed. Clinical findings in common across the six adult 2q13 duplication carriers in this study included: dental (ectopic teeth/dental crowding, otologic (hearing loss), urogenital abnormalities (cryptorchidism), and short stature, in addition to later-onset psychiatric illness.
21255006 Yu et al. (2012) describe one individual (Case 5) with a duplication of the recurrent 2q13 (BCL2L11) region. Clinical findings in this patient included ASD, mild hypotonia with diminished strength, and mild developmental delay. Parental testing was not performed. The authors review genetic, clinical and inheritance data for this newly reported case, as well as four others characterized by genomic microarray (five cases total), including one case (16) from the DECHIPER database, one case (17) from a large-scale study of autism risk loci (Szatmari et al., 2007), and two cases previously reported by Rudd et al. (2009, cases 18 and 19) (Table 3). Though limited in number, the majority of individuals with this duplication had developmental delays and dysmorphic features. There was no parental testing in any of the reported cases. The authors note that Rudd et al. (2009) identified 2q13 duplication in 1/876 control individuals suggesting that the duplication has incomplete penetrance.

Triplosensitivity phenotype comment:

At least six unrelated patients with 2q13 duplications* have been reported in the literature. Amongst affected carriers, clinical findings are variable, including developmental delay, tooth abnormalities, hypotonia, and neuropsychiatric conditions. In all reported cases thus far, 2q13 duplications have been found to be inherited; affected status varies across carrier parents. Statistical significance has been observed from case-control comparison (reviewed below), though observed duplications in both populations are rare. Due to phenotypic variability and inheritance information, the current haploinsufficiency score is 2. *The proximal 2q 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 breakpoints within the 2q13 region (BCL2L11 included). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional relevant literature is summarized below: Case-control studies PMID: 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, duplications of the recurrent 2q13 (BCL2L11) region were observed in 7/29,085 cases versus 0/19,584 controls (p=0.027; LR=Inf, CI: 1.23 to Inf), demonstrating enrichment of this duplication in the clinical population. See also Cooper et al. (2011), PMID 21841781. Additional cases PMID: 19443486 Rudd et al. (2009) analyzed array CGH data of 2419 individuals in an effort to identify new syndrome associated segmental duplication-mediated chromosome rearrangements. This study described two individuals (patients 3 and 4, table 1) with duplications of the recurrent 2q13 (BCL2L11) region. These individuals had clinical features that were non-specific; however, dental anomalies were observed in both individuals. Both duplications were paternally inherited (no clinical data was available). The duplication also was identified in 1/876 control individuals, which included 347 unaffected parents of schizophrenia probands and 529 Ashkenazi Jewish patients with Crohn?s disease, dystonia or Parkinson?s disease (n=876).