Molecular analysis of SALL1 mutations in Townes-Brocks syndrome

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformat ion syndrome characterized by anal, renal limb, and ear anomalies. Recently , we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 addi tional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previo usly been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc fi nger (DZF) encoding region and are therefore predicted to result in putativ e prematurely terminated proteins lacking all DZF domains. This suggests th at only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do no t seem to depend on the site of mutation.