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Select assembly: (NC_000019.9) (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
30758909 Glass et al (2019) present a series of 16 unrelated probands (and 20 additional family members) with ERF-related craniosynostosis. This paper is a followup to the group's first ERF craniosynostosis paper (Twigg et al 2013 - see below) - but all families in this paper were new. All probands had radiologically confirmed craniosynostosis and most probands exhibited multisutural synostosis involving sagittal and lambdoid sutures. Importantly the craniosynostosis was often postnatal in onset, and progressive with subtle effects on head morphology resulting in a median presentation age of 42 months. A number of additional phenotypic features were common and included visual impairment, facial dysmorphism, speech delay, poor motor control, hyperactivity and poor concentration. Variable expressivity and nonpenetrance was observed in some family members, consistent with previous reports. The series included 13 different variants in the 16 apparently unrelated probands (but shared variant families originated from the same broad geographical area): 1 de novo, 4 inherited and 2 unknown LoF variants (1 segregation) 6 inherited missense variants (10 segregations) 1 variant in translation initiation codon All missense variants occurred in highly conserved residues of the DNA-binding ETS domain of the ERF protein between amino-acids 29 and 106. All LoF variants were located further towards the C-terminus and predicted to cause loss of the repressor domain, or ERK interaction and repressor domains, if they did not result in nonsense mediated mRNA decay.
23354439 Twigg et al (2013) report a series of 12 probands (and 26 familiy members) with ERF-related craniosynostosis. All probands had craniosynostosis and most had facial dysmorphism and behavioral or learning problems, particularly affecting concentration and language acquisition. Most carrier parents only had mild craniofacial signs or macrocephaly suggesting variable expressivity/nonpenetrance. 1 de novo, 6 other LoF variants (2 segregations) 2 de novo, 1 inherited missense variant (1 segregations) 1 de novo variant in translation initiation codon The missense variants were located in critical residues in the DNA-binding ETS domain. Mice were engineered to express 30% of wild-type level Erf (heterozygotes had no phenotype and homozygous knockouts did not survive). These mice had craniosynostosis affecting multiple sutures.
26097063 Chaudhry et al (2015) sequenced ERF in 40 patients with multiple suture or sagittal craniosynostosis and identified two variants: c.1A>G and c.23?2A>G. Other phenotypic features included facial dysmorphism, speech delay and presentation at 6 yrs of age. Forty patients with multi-suture or sagittal suture synostosis were sequenced. Heterozygous ERF mutations, predicted to be inactivating (M1? variant and canonical slice acceptor variant), were found in two individuals. Clinical features of the patients included pansynostosis, bilateral coronal and metopic synostosis. Other features included dysmorphisms consistent with previous cases. Parental samples were not available for study.
29215649 Lee et al (2018) describe a prospective clinical cohort of 76 patients with nonsyndromic and syndromic craniosynostosis, tested using an NGS panel of 20 genes. 1 LoF and 1 missense ERF variant were detected. An addtional retrospective cohort of 233 patients, previously tested for hotspots in FGFR1, FGFR2, FGFR3 and TWIST1 were also tested with the 20 gene panel and a further ERF LoF variant was detected.

Haploinsufficiency phenotype comments:

Prevalence of ERF variants in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis, Wilkie et al (2017) doi: 10.1097/MOP.0000000000000542. Most probands exhibit multisutural synostosis and the craniosynostosis is often postnatal in onset, resulting in presentation at ~4yrs on average. Facial dysmorphism is a common feature, as well as speech delay. Variable expressivity and nonpenetrance among genetically affected relatives is well documented.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity