Molecular Characteristics:RCPS is caused by an expansion in the 5´UTR of the EIF4A3gene in the 17q25.3 chromosomal region. Most affected individuals are homozygous for an increased number of repeats (14 or 16 repeats) composed of 18- or 20-nucleotide motifs. In patients, the 20-nucleotide motif differs from that of controls by a single G nucleotide. In all tested cases, these alleles were inherited from heterozygous parents. Affected individuals who are homozygous for 14 repeats, or compound heterozygous for EIF4A3(one allele with 14 repeats and the other carrying a point mutation, c.809A>G), present with a milder Richieri-Costa-Pereira syndrome phenotype. This is the only reported case so far involving a missense variant.
Pathophysiological mechanism:EIF4A3encodes the protein EIF4A3, a core component of the exon junction complex (EJC). It plays roles in regulating downstream processes of mRNA splicing, nonsense-mediated mRNA decay (NMD) and rRNA biogenesis, among others. Reduced expression of EIF4A3 leads to defective neural crest cell migration and differentiation, as well as neural stem cell apoptosis during embryonic development.
Diagnostic test:For the cases with typical or overlapping phenotype with RCPS is recommended : Sanger sequencing of region containing the repeat motifs in 5´UTR of EIF4A3; if negative exome sequencing is recommended to search for missense variants. Genomic sequencing can detect both types of variants.
Genetic Counseling:RCPS is an autosomal recessive condition, and the recurrence risk is 25% to parents of an affected individual. Therefore, confirmation of the clinical hypothesis is very important.
EIF4A3