ClinGen Dosage Sensitivity Curation Page

15q25.2q25.3 recurrent region (LCR C-D, distal)

  • Curation Status: Complete
  • id: ISCA-37514
  • Date last evaluated: 2020-06-26
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 1
  • ClinGen Triplosensitivity Score: 0


Location Information

  • 15q25.2-q25.3
  • GRCh37/hg19 chr15: 85,139,652-85,713,001
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr15: 84,596,421-85,169,770
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000015.9) ()
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
23239641 Doelken, et al. (2013) described a male patient with three microdeletions, including a microdeletion of the 15q25.2q25.3 region (LCR C-D, distal). He had severely delayed psychomotor and language development, epileptiform signs by EEG, plagiocephaly, microcephaly, dysmorphic craniofacial features (which included strabismus, myopathic facies, hypoplastic nasal alae, bitemporal sparse hair), camptodactyly of the 5th fingers, left-sided retractile testis, and recurrent infections. The 15q25.2q25.3 deletion was inherited from a healthy father. Additionally, this patient had a 1q21.1 deletion (maternal inheritance) and a de novo hemizygous deletion of the Xq12 region (including OPHN1). Therefore, the authors acknowledge that the patient's clinical findings might be the result of the combination of the three microdeletions.

Haploinsufficiency phenotype comments:

Few published reports of 15q25.2q25.3 region (LCR C-D, distal) deletion* exist in the literature; however, statistical enrichment has been observed from case-control comparison (reviewed below). Therefore, the current haploinsufficiency score is 1. *The distal 15q 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 15q25.2q25.3 region (LCR C-D, distal) 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 15q25.2q25.3 region (LCR C-D, distal) we observed in 7/29,085 cases versus 0/19,584 controls (p=0.0272; LR=Inf, CI: 1.23 to Inf), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2014), PMID 21841781. PMID: 21841781 Cooper, et al. (2011): In a large-scale case-control comparison study of CNVs in 15,767 children with developmental and intellectual disability, five patients were described with microdeletions of 15q25.2q25.3. Three of these patients were described to have developmental delay (one also had a seizure disorder), one had autism, and one had muscle weakness. The inheritance is unknown for 4 of the patients and maternally inherited for one. PMID: 19166990 Itsara, et al. (2009) analyzed the combined data from three population studies composed of approximately 2500 individuals. Four affected patients (two with autism and two with schizophrenia) were identified with deletions in 15q25.2q25.3. Comparison between the case and control data did not reach statistical significance.

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

Triplosensitivity phenotype comment:

As yet, no published reports of 15q25.2q25.3 region (LCR C-D, distal) duplication* exist in the literature and statistical enrichment has not been observed from case-control comparison (reviewed below). Therefore, the current triplosensitivity score is 0. *The distal 15q 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 15q25.2q25.3 region (LCR C-D, distal) 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 15q25.2q25.3 region (LCR C-D, distal) we observed in 2/29,085 cases versus 0/19,584 controls (p= 0.3570; LR=Inf, CI: 0.175 to Inf), demonstrating a lack of enrichment of this duplication in the clinical population. See also Cooper et al. (2014), PMID 21841781.