Novel frameshift variant in gene SALL4 causing Okihiro syndrome

Okihiro syndrome, Duane-radial ray syndrome or acro-reno-ocular syndrome (OMIM #607323) are alternative denominations describing an extremely variable condition, characterized by several radial defects of the upper limbs associated with Duane anomaly. It is a rare autosomal dominant disorder determined by variants in the SALL4 gene which encodes a transcription factor with eight zinc finger motifs. Here we report a novel heterozygous frameshift variant, c.410dupG, present in a Brazilian family. The five affected individuals exhibit a broad spectrum of phenotypes, ranging from the severe one presented by the index case (grossly shortened and deformed forearm, markedly hypoplastic and appendicular thumb, malformed right foot and ear malformation), to the less conspicuous condition presented by his near relatives (usually only triphalangeal or hypoplastic thumbs, sometimes associated with ulnar deviation); Duane's anomaly, however, was not observed in any of the affected family members. The c.410dupG variant is predicted to result in the translation of a truncated protein with 180 amino acid residues, lacking seven of the eight zinc finger motifs, with the same size of the predicted products of the already reported c.496dupC variant, described in two unrelated cases. However, the phenotypes observed in the three families (the one here reported and other two with c.496dupC variant) are very different. The analysis of cases so far published does not permit to establish a clear or direct genotype-phenotype correlation, but the three more severe foot malformation cases are due to variants predicted to encode truncated proteins lacking seven ZFMs. This might indicate a possible correlation between foot malformation and reduced size of the protein, suggesting that the nonsense-mediated-decay mechanism might not be so effective as to eliminate all SALL4 variants harboring premature termination codons.