ClinGen Dosage Sensitivity Curation Page

10q22.3q23.2 recurrent region (LCR-3/4-flanked) (includes BMPR1A)

  • Curation Status: Complete
  • id: ISCA-37424
  • Date last evaluated: 2016-10-13
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1


Location Information

  • 10q22.3-q23.2
  • GRCh37/hg19 chr10: 81,682,843-88,739,388
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr10: 79,923,087-86,979,631
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000010.10) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
20345475 Alliman et al. (2010) provide a clinical description of four individuals with 7.25 Mb deletions spanning 10q22.3q23.2 (hg18 81.7-88.9 Mb). Deletions were identified by oligo microarray analysis and were flanked by LCRs. Parental FISH results indicated that these deletions were apparently de novo in all four patients. Common phenotypic features include: developmental delay, language delay, and dysmorphic features (such as hypertelorism and low-set ears).
21248748 van Bon et al. (2011) summarize five individuals with deletions spanning 10q22.3q23.2 (hg18 81.6-89.1 Mb, liftover hg19 81.6-89.1 Mb). Deletions were identified by various oligo microarray platforms. They were subsequently fine-mapped using a custom high-resolution array and were flanked by LCR3/4. One patient had an additional de novo CNV and another patient had a 47,XYY karyotype. The 10q22.3q23.3 deletion was found to be de novo in 3/5 cases, inherited from a mother who underwent special-schooling in one case, and of unknown inheritance in the last case. Common phenotypic features include: developmental delay, speech delay, and dysmorphic features (such as hypertelorism and low-set ears). Other anomalies were sometimes observed (e.g. cardiac findings, brain findings, hand abnormalities).
24550761 Petrova et al. (2014) report a case of a boy with a de novo LCR3/4-flanked 10q22.3q23.2 deletion who was determined to have age-appropriate language development at age 2 years 3 months. The boy had a congenital heart defect, a club foot, cleft palate, hypertelorism, and other dysmorphic features.

Haploinsufficiency phenotype comments:

10q22.3q23.2 deletions are approximately 7Mb in size, and include genes NRG3, GRID1 and BMPR1A. These deletions appear to be almost always de novo, and are associated with developmental delay and craniofacial asymmetry; congenital anomalies are less frequent but may include facial clefting, cardiac and/or hand/foot anomalies. 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 10q22.3q23.2 (LCR-3/4-flanked) region were observed in 11/29,085 cases versus 0/19,584 controls (p=0.0035; LR=Inf, CI: 2.21 to Inf), demonstrating enrichment in the clinical population. See also Cooper et al. (2011), PMID 21841781.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
21248748 van Bon et al. (2011) also summarize two unrelated patients with duplications spanning 10q22.3q23.2 (hg18 81.6-89.1 Mb, liftover hg19 81.6-89.1 Mb). Duplications were identified by various oligo microarray platforms. They were subsequently fine-mapped using a custom high-resolution array and were flanked by LCR3/4. In one patient the 10q22.3q23.2 duplication was de novo and this patient had an additional de novo CNV. The other patient inherited the 10q22.3q23.2 duplication (parental phenotype not available). Common phenotypic features include: developmental delay, and dysmorphic features (such as deep set eyes and thin upper lip).
26383923 Tang et al. (2015) report a boy with an apparently de novo 10q22.3q23.2 duplication (hg19 80.6-88.7 Mb) observed by both chromosome analysis and SNP microarray. His phenotype included: funnel chest, difficulty pronouncing words, atrial septal defect, growth retardation, a head circumference <3rd centile, and dysmorphic features (including a thin upper lip).

Triplosensitivity phenotype comment:

Duplications have been only rarely reported and as a result, the phenotype remains uncertain. 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 10q22.3q23.2 (LCR-3/4-flanked) region were observed in 4/29,085 cases versus 0/19,584 controls (p=0.1280; LR=Inf, CI: 0.559 to Inf), demonstrating a lack of enrichment in the clinical population. See also Cooper et al. (2011), PMID 21841781.