ClinGen Dosage Sensitivity Curation Page

15q13 recurrent region (BP3-BP4) (includes APBA2)

  • Curation Status: Complete
  • id: ISCA-46285
  • Date last evaluated: 2020-03-09
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: 0


Location Information

  • 15q13.1-q13.2
  • GRCh37/hg19 chr15: 29,156,959-30,368,990
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr15: 28,916,886-30,076,787
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000015.9) ()
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
21248749 Rosenfeld et al. (2011) reported three unrelated probands (Subjects 1-3) with deletion of the 15q13 (BP3-BP4) region identified by routine aCGH testing and compared clinical findings to BP3-BP4 patients previously reported in the literature, as well as a patient (Subject 4) with an atypical BP3-BP4 deletion (partially overlapping this region). Clinical findings in more than 50% of BP3-BP4 deletion carriers, summarized in Table 2, include DD/ID (7/7), hypotonia (5/6), ocular features (5/6), dysmorphic features (6/7), failure to thrive (4/6), short stature (4/7), and microcephaly (4/7). The authors note, through genotype-phenotype correlation, that certain features seen in association with the larger BP3-BP5 deletion may be attributed to the BP3-BP4 region. The deletion of Subject 2 was de novo, while the deletion of Subjects 1 and 3 were inherited from mothers who were clinically unaffected. Other patients from the literature have inherited deletions. Two deletions were reported in control cohorts. Enrichment studies failed to show a statistically significant enrichment of these deletions. The authors note, ?a comparison of these cases with each other and with those in the literature shows some phenotypic similarities?we propose that deletions of the BP3?BP4 interval can contribute to an abnormal phenotype. However, there is still phenotypic variability among subjects, and a consistent and recognizable phenotype is not present.?
19372089 van Bon et al. (2009) reported clinical findings of a proband (Patient 19) with deletion of the 15q13 (BP3-BP4) region, which included failure to thrive, hypotonia, microcephaly, craniofacial dysmorphism. This deletion was paternally inherited (father with normal cognitive function) and was also present in a 5-year-old brother and paternal uncle, who both had normal development. Another brother, aged 4, also had ID and did not have the BP3-BP4 deletion, demonstrating evidence of non-segregation. The authors note, ?The limited data so far indicate that the BP3?BP4 deletion is a novel copy number variation of doubtful clinical significance, especially as the phenotype of both the BP3?BP5 cases (case 16 and 17) was not more severely affected than that of patients with a deletion comprising BP4?BP5 only.?
18278044 Sharp et al. (2008) reported clinical findings of a proband (Individual 543/06) with deletion of the 15q13.3 (BP3-BP4) region, which included developmental delay, dysmorphic features (including iris coloboma), and a kidney anomaly (ureteral ectasia). The deletion was inherited from the unaffected father of this patient. The authors state, ?Therefore, we interpret this BP3-BP4 deletion as probably representing a benign copy number variant, although we cannot exclude that it may instead be a pathogenic deletion with incomplete penetrance.?

Haploinsufficiency phenotype comments:

Deletion of the 15q13 BP3-BP4 region* has been reported in at least 5 unrelated patients with relatively nonspecific clinical phenotypes (summarized by Rosenfeld et al., 2011). In 4 cases, the deletion was inherited from a clinically unaffected parent, and in the family reported by van Bon, multiple unaffected carriers, as well as an affected non-carrier sibling, were reported. Deletion of the BP3-BP4 region is rare; this deletion is not enriched in the clinical population and has been observed (rarely) in individuals in control databases (DGV and gnomAD). Currently there is not enough evidence supporting nor refuting the clinical significance of deletion of this region; therefore the haploinsufficiency score is 0. *The 15q11.2-q14 region contains a cluster of low copy repeats (LCRs), referred to as breakpoint (BP) regions 1 through 6 (BP1 to BP6), that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to deletions involving the region between BP3 and BP4, located in 15q13. Note that a variety of LCR-mediated rearrangements are possible, and CNVs overlapping this region should be evaluated based on reports of patients with similar genomic content. Note also that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. 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 15q13 (BP3-BP4, APBA2 included) region were observed in 6/29,085 cases versus 1/19,584 controls (p=0.1555; LR: 4.04, CI: (0.585 to 58.5)), demonstrating a lack of enrichment of this deletion in the clinical population.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Duplication of the 15q13 BP3-BP4 region* has not yet been reported in association with clinical findings. Therefore the current triplosensitivity score is 0. *The 15q11.2-q14 region contains a cluster of low copy repeats (LCRs), referred to as breakpoint (BP) regions 1 through 6 (BP1 to BP6), that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to duplications involving the region between BP3 and BP4, located in 15q13. Note that a variety of LCR-mediated rearrangements are possible, and CNVs overlapping this region should be evaluated based on reports of patients with similar genomic content. Note also that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. 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 15q13 (BP3-BP4, APBA2 included) region were observed in 5/29,085 cases versus 2/19,584 controls (p= 0.4147; LR:1.68, (0.329-10.7)), demonstrating a lack of enrichment of this duplication in the clinical population.