Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum

The SALL genes, similar to the Drosophila gene spalt, 1 encode likely zinc finger transcription factors.In humans, four such genes have been identified to date.Mutations in the gene SALL1 on chromosome 16q12.1 have been associated with Townes-Brocks syndrome and related phenotypes, 2 3 and mutations in the gene SALL4 have been shown to be causative in patients with Okihiro syndrome. 4 5SALL2 6 and SALL3 7 remain to be associated with human disease.We previously reported frameshift and nonsense mutations in SALL4 in five of eight families segregating the Okihiro syndrome phenotype. 5A further report 4 identified two frameshift mutations and one nonsense mutation in three affected kindreds, including the family reported by Okihiro et al. 8 In a recent study of patients with a clinical diagnosis of Holt-Oram syndrome, one additional frameshift mutation and an unclear missense change were reported from a family who turned out to have Okihiro syndrome rather than Holt-Oram. 9Furthermore, we reported one previously identified and three novel SALL4 mutations in patients originally diagnosed as having either Holt-Oram syndrome (later revised to Okihiro syndrome based on the observation of a Duane anomaly in at least one of the affected family members in each family), acro-renal-ocular syndrome, or Holt-Oram syndrome versus thalidomide embryopathy. 10While our findings suggested that acro-renal-ocular syndrome and Okihiro syndrome are allelic, evidence so far has come only from one family in which no gross structural eye defects were seen. 11In order to further substantiate our findings we sought to perform mutation analysis in additional patients diagnosed with acro-renal-ocular syndrome, especially those who presented with structural eye defects.We were also interested in extending our studies to further patients with Okihiro syndrome in order to allow a genotype-phenotype correlation.Here we report five novel SALL4 mutations from five unrelated families, three nonsense and two frameshift mutations.Previous clinical diagnosis was Holt-Oram syndrome, Okihiro syndrome, or Townes-Brocks syndrome, in each of three families, and acrorenal-ocular syndrome in a further two families.