ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000014.8) (NC_000014.9)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21340693 Reis (2011): Report includes one patient with anophthalmia/microphthalmia, diaphragmatic hernia, facial asymmetry, and hydrocephalus who had a de novo nonsense mutation. This mutation was previously reported in a patient with orofacial clefting (Suzuki, 2009). Also, two maternal half-siblings with anophthalmia and other anomalies were found to have a frameshift mutation. This was inherited from the mother who had not had a ophthalmologic examination. No maternal mosaicism was detected but maternal grandparental studies were normal, indicating that the mutation arose de novo in the mother. Another patient with microphthalmia, intellectual disability, and dysmorphic facial features was found to have a focal deletion affecting BMP4 alone but parental studies were not available. They also report another patient with SHORT syndrome and a larger deletion including BMP4 and other genes.
18252212 Bakrania (2008): Report includes one family with a frameshift mutation that segregates through three generations with ophthalmologic abnormalities, CNS anomalies, and polydactyly. Two other patients with anophthalmia/microphthalmia and large cytogenetic deletions including BMP4 and other genes are included, and other patients with missense mutations were identified.

Haploinsufficiency phenotype comments:

Large deletions including BMP4 and other genes have been reported in patients with anophthalmia/microphthalmia. Nolen et al (2006), PMID: 16835935, report one patient with anophalmia, pituitary hypoplasia, and ear anomalies who had a de novo t(3;14)(q28;q23.2) with a deletion at the 14q breakpoint that includes BMP4 and many other genes. Suzuki (2009, PMID: 19249007) also reports a patient with cleft lip/palate who the same nonsense mutation reported in Reis et al (2011), but parental genotype and phenotype was not available. Other sequence variants were also identified in patients with clefting defects or microform that were not identified in controls. Additionally, Lubbe et al (2011), PMID: 20949628, report one individual with a truncating mutation who had early-onset colon cancer. This individual was apparently not evaluated specifically for congenital anomalies but none were documented in her care.

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