ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

ERF is a developmentally important transcription regulator. Studies of patients with craniosynostosis have found approximately 3-5% of cases have a heterozygous pathogenic (nonsense or frameshift) ERF mutation. There seems to be variable expressivity as some cases have been inherited from a mildly affected parent (such as hypertelorism or macrocephaly). Missense mutations appear to cause a different phenotype, known as Chitayat syndrome: bronchomalacia (weak cartilage in the walls of the brachial tubes), craniofacial asymmetry and digital anomalies. The score is currently set at 2 due to incomplete information regarding heritability (parental phenotypes and de novo occurrences).

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