ClinGen Dosage Sensitivity Curation Page

EFNB1

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
15166289 Twigg et al. (2004) report mutations in 20 unrelated females with craniofrontonasal dysplasia including 2 nonsense (one de novo, one inheritance not tested), one familial frameshift, and two invariant splice site mutations (one de novo, one inheritance not tested). X-inactivation was found to be normal in blood and cranial periosteum. Clinical descriptions are also provided by Orr et al., PMID: 9176000.
15124102 Wieland et al. (2004) report one family with three females with craniofrontonasal dysplasia and two males with hypertelorism who had a deletion of exons 2-5 in EFNB1. Two other reported families had missense mutations.
15959873 Wieland et al. (2005) screened 38 unrelated females with craniofrontonasal dysplasia and found 15 frameshift mutations, 7 nonsense mutations, and 2 splice site mutations. They propose cellular interference between cells with and without the mutation as a mechanism for the clinical severity seen in females.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
21064195 Srisupundit et al (2010) report a male baby who died of complications related to congenital diaphragmatic hernia who had a 340 kb focal duplication of EFNB1. Parental testing was declined. The authors speculate on the possible pathogenicity of this duplication since congenital diaphragmatic hernia can be seen in female patients with craniofrontonasal dysplasia.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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.