Craniosynostosis
Gene: EFNA4
Supporting animal models, but no compelling evidence in human cases has been reported since 2006. There’s no supporting segregation evidence and most of the variants reports to date are more common than expected for a dominant disease.
PMID: 34586326 - 3 missense variants identified in a cohort of 101 children with non-syndromic craniosynostosis (EFNA4, c.178C>T: p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1, c.283A>G: p.Lys95Glu, c.349C>A: Pro117Thr - 337 hets in gnomAD v2.1). All 3 variants were present in at least one non-affected family member
PMID: 23983218, 33065355 - Efna4 KO mouse line demonstrates skeletal variance. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls
PMID: 29215649 - 1 missense variant (c.211G>A, p.(Glu71Lys) - 7 hets in gnomAD v2.1) identified in a unicoronal craniosynostosis case in a cohort of 309 craniosynostosis cases
PMID: 29168297 - 1 missense variant (c.550C>T; p.(Leu184Phe) - 1 het in gnomAD v2.1) in a metopic craniosynostosis case from a cohort of 391 single suture craniosynostosis cases. The variant was inherited from an unaffected parent.
PMID: 19772933 - a de novo 1.4 Mb microdeletion of chromosome 1q21.3, including EFNA1, EFNA3 and EFNA4, was identified in a child with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly.
PMID: 19201948 - EphA4 -/- mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1+/- mice. The EphA4 +/- mice were similar to the wild-type controls.
PMID: 16540516 - 3 variants (178C>T p.His60Tyr - 361 hets & 2 homs in gnomAD v2.1; c.349C>A p.Pro117Thr - 337 hets in gnomAD v2.1; frameshift 471_472delCCinsA) in cohort of 81 non-syndromic coronal synostosis cases. 2 of the variants were inherited from unaffected parents and Pro117Thr was de novo (confirmed). In vitro functional assays demonstrated partial or complete loss of function for the missense variants. Fibroblasts from the patient with the frameshift expressed in an alternatively spliced minor isoform of EFNA4.Created: 12 Apr 2025, 6:30 a.m. | Last Modified: 12 Apr 2025, 6:30 a.m.
Panel Version: 1.68
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
craniosynostosis MONDO:0015469
Publications
Two unrelated individuals from two craniosynostosis cohorts with variants in EFNA4. 29168297 also reports variants in 4 craniosynostosis cases but acknowledges that causality is not proven.Created: 3 Jun 2020, 12:03 p.m. | Last Modified: 3 Jun 2020, 12:03 p.m.
Panel Version: 0.27
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Coronal and metopic craniosynostosis
Publications
Gene: efna4 has been classified as Red List (Low Evidence).
Phenotypes for gene: EFNA4 were changed from to Coronal and metopic craniosynostosis
Publications for gene: EFNA4 were set to
Mode of inheritance for gene: EFNA4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: efna4 has been classified as Amber List (Moderate Evidence).
Gene: efna4 has been classified as Amber List (Moderate Evidence).
gene: EFNA4 was added gene: EFNA4 was added to Craniosynostosis_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: EFNA4 was set to Unknown