ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.