Craniofrontonasal Syndrome via the EFNB1 Gene

EFNB1-related craniofrontonasal syndrome is mainly characterized by hypertelorism, broad nasal tip, brachycephaly, coronal suture synostosis, strabismus, frontal bossing, bifid nasal tip, and high-arched palate. Some less common features include asymmetric lower limbs, grooved nails, thick/wiry hair, webbed neck/short neck, cleft lip and/or palate, and corpus callosum hypoplasia or agenesis. Over 98% of patients had normal mental development (Wieacker and Wieland 2005).

EFNB1-related craniofrontonasal dysplasia shows an unusual X-linked inheritance pattern. Heterozygous female patients generally present more severe clinical features than hemizygous male patients (Wieland et al. 2005). Male patients may only have hypertelorism, however, a few males mosaic for an EFNB1 pathogenic variant had severe clinical presentations (Twigg et al. 2013). The EFNB1 protein is a member of the ligand of Eph-related receptor tyrosine kinases, which may play roles during embryonic morphogenesis. Over 100 EFNB1 pathogenic variants have been reported. They include: missense (37%), nonsense: (10%), splicing (10%), small deletion/insertions (33%), gross deletion/insertion (10%) and one pre-coding point pathogenic variant (Wieland et al. 2005; Twigg et al. 2006; Twigg et al. 2013; Human Gene Mutation Database). Wieland et al. studied 9 familial and 29 sporadic craniofrontonasal dysplasia patients and identified pathogenic variants in 8/9 familial cases and 25/29 sporadic cases, respectively. De novo variants were seen in 6 out of the 25 sporadic cases. The c.196C>T (p.Arg66*) variant was seen in one familial and four sporadic cases (Wieland et al. 2005).

EFNB1 pathogenic variants were detected in 33 out of 38 unrelated clinical suspected craniofrontonasal dysplasia patients (Wieland et al. 2005).

This test provides full coverage of all coding exons of the EFNB1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).