Limb disordersGene: EIF4A3
Gene suggested for the panel
Created: 1 Aug 2019, 5:10 p.m. | Last Modified: 1 Aug 2019, 5:10 p.m.
Panel Version: 1.24
PMID: 10594883 - Walter-Nicolet et al 1999 - report a French boy with phenotype similar to Richieri-Costa and Pereira form of acrofacial dysostosis but no genome analysis done.
PMID: 29112243 - Bertola et al 2018 - describe 5 (4 Brasilian, one from England, of African ancestry) new individuals with Richieri-Costa-Pereira syndrome. The patient from England/Kenya showed limb abnormalities of Hypoplastic hallux and club feet only. Expansions of the repeated motif in the 5′ UTR of EIF4A3 were found in all individuals and ranged from 14 to 16 repeats.
Created: 25 Nov 2019, 11:27 p.m. | Last Modified: 26 Nov 2019, 4:14 p.m.
Panel Version: 1.127
Comment on list classification: Relevant phenotype, however potential founder effect in the Brazilian population described to date. The phenotype of the patient from England/Kenya is borderline for this panel. Further evidence needed therefore rating amber. Rating agreed with Genomics England clinical team.
Created: 25 Nov 2019, 11:03 p.m. | Last Modified: 29 Nov 2019, 9:54 a.m.
Panel Version: 1.135
Associated with Robin sequence with cleft mandible and limb anomalies (#268305) in OMIM and RICHIERI-COSTA-PEREIRA SYNDROME in Gene2Phenotype (confirmed, 5_prime or 3_prime UTR mutation).
PMID: 24360810 - Favaro et al. 2014 - found in Brazilian families with RCPS 17 affected probands were homozygous for the 16-repeat allele in the 5 prime UTR of EIF4A3, and 3 apparently unrelated affected individuals were compound heterozygotes (15 or 16 repeats). All tested parents were heterozygous for the 16-repeat allele, and unaffected siblings either lacked the expanded allele or were heterozygotes. The 15- and 16-repeat allele haplotypes spanning EIF4A3 are consistent with a common origin and corroborate their previous founder effect hypothesis for most Brazilian RCPS-affected individuals. Sequencing of EIF4A3 in five additional Brazilian affected individuals ascertained elsewhererevealed that four of them (, including 2 siblings) were homozygous for the 16-repeat allele. In contrast, the fifth (individual 25) was a compound heterozygote, possessing a 14-repeat allele in trans with a nucleotide change, c.809A>G, p.Asp270Gly. the c.809A>G mutation is embedded in a distinct haplotype, suggesting multiple pathogenic mutational origins in EIF4A3.
EIF4A3 transcript abundance was about 30%–40% lower in affected individuals than in controls in both cell types tested.
Zebrafish morpholinos show underdevelopment of craniofacial cartilage, bone alterations, and clefting of the lower jaw.
Created: 18 Aug 2019, 11:32 a.m. | Last Modified: 18 Aug 2019, 11:32 a.m.
Panel Version: 1.58
Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust
Sources: Expert list
Created: 1 Aug 2019, 1:40 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Robin sequence with cleft mandible and limb anomalies, 268305
Gene: eif4a3 has been classified as Amber List (Moderate Evidence).
gene: EIF4A3 was added gene: EIF4A3 was added to Limb disorders. Sources: Expert list Mode of inheritance for gene: EIF4A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EIF4A3 were set to 9284755; 9449664 Phenotypes for gene: EIF4A3 were set to Robin sequence with cleft mandible and limb anomalies, 268305 Review for gene: EIF4A3 was set to AMBER