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
23354439 Reduced dosage lead to complex craniosynostosis in humans and mice. Features of this clinical disorder include multiple suture synostosis, craniofacial dysmorphism. Mutations in humans are heterozygous and inactivating. The authors report reduced protein expression via immunoblot for an initiation codon variant and two nonsense variants. The initiation codon variant was apparently de novo, the nonsense variants segregated with familial disease. Gene has been assigned to Craniosynostosis Type 4 in OMIM (OMIM 600775).
26097063 Forty patients with multi-suture or sagittal suture synostosis were sequenced. Heterozygous ERF mutations, predicted to be inactivating (M1? variant and canonical slice acceptor variant), were found in two individuals. Clinical features of the patients included pansynostosis, bilateral coronal and metopic synostosis. Other features included dysmorphisms consistent with previous cases. Parental samples were not available for study.

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.