ERF – ERF-related Craniosynostosis 4

Heterozygous loss-of-function variants in ERF underlie autosomal dominant craniosynostosis 4. In a multigenerational family, exome sequencing identified a truncating frameshift variant c.1201_1202del (p.Lys401GlufsTer10) in a boy and his mother, both exhibiting trisutural synostosis and intracranial hypertension confirmed by invasive monitoring (PMID:32370745). Segregation of the variant with disease in the two affected individuals supports pathogenicity of ERF haploinsufficiency in cranial suture homeostasis.

Functional studies of ERF truncating and missense alleles demonstrate disrupted ERF–ERK1/2 interaction and impaired transcriptional repression of osteogenic targets. Truncating variants localize predominantly to the nucleus, lose repression of osteoblast proliferation in MC3T3-E1 cells, and exhibit reduced RUNX2-motif reporter suppression in luciferase assays (PMID:39668184; PMID:40307313). Concordant cellular phenotypes confirm a haploinsufficiency mechanism for ERF in cranial suture fusion.

Key Take-home: Genetic testing for ERF truncating variants is clinically actionable in autosomal dominant craniosynostosis 4 to guide surveillance for intracranial hypertension and surgical planning.

References

• BMC medical genetics • 2020 • A progressive and complex clinical course in two family members with ERF-related craniosynostosis: a case report. PMID:32370745
• European journal of human genetics : EJHG • 2024 • Heterozygous variants disrupting the interaction of ERF with activated ERK1/2 cause microcephaly, developmental delay, and skeletal anomalies. PMID:39668184
• Scientific reports • 2025 • Missense and truncated variants in ERF in individuals with a Noonan-like phenotype without craniosynostosis. PMID:40307313

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