ClinGen Dosage Sensitivity Curation Page

EFNB1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Loss of function mutations are associated with craniofrontonasal dysplasia in females, regardless of X-inactivation patterns. Males with mutations have hypertelorism but do not have the associated skeletal findings or other features. Other papers describing mutations include PMIDs 20734337, 21385071, 18627045, 16526919.

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.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function 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.

Triplosensitivity phenotype comment:

Non-focal duplication involving EFNB1 have been reported. Petit et al (2011) describe a boy with congenital diaphragmatic hernia, speech and mild motor delays, and dysmorphic facial features including hypertelorism who had a 1.3 Mb de novo duplication of 5 genes, including EFNB1. Babbs et al (2011) report a family with a female proband who had short stature, mild developmental delay, dysmorphic facial features including hypertelorism, and mild nail ridging who had a 937 kb duplication of EFNB1 and 2 other genes. This was inherited from the mother who had hypertelorism and nail ridging and was present in the maternal grandmother who had hypertelorism. Sequencing of EFNB1 was normal. Similar duplications have also been reported in normal children (Shaikh et al., 2009, PMID: 19592680, http://cnv.chop.edu).

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.