ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-1397
• Date last evaluated: 2017-04-13
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/2077
• OMIM: https://omim.org/entry/611888

Location Information

• 19q13.2
• GRCh37/hg19 chr19: 42,751,713-42,759,316

Evidence for Loss Phenotypes

• Loss of function score: 2
• Strength of Evidence: Some evidence for dosage pathogenicity

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.

• Loss of function 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).

Evidence for Triplosenstive Phenotype

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

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.