Editor—Townes-Brocks syndrome (TBS, MIM 107480) was first described by Townes and Brocks1 in 1972 as an association of imperforate anus, supernumerary thumbs, malformed ears, preauricular tags, and sensorineural hearing loss. Several additional familial as well as isolated cases have been reported.2 TBS is caused by mutations of the putative zinc finger transcription factor geneSALL1.3 AllSALL1 mutations identified to date in TBS patients are located 5′ of the first double zinc finger encoding region.4 Three of these are nonsense mutations at two different positions. The mutation 826C>T was found in three unrelated sporadic cases, and at position 1115 one patient carried an adenine (1115C>A) and another a guanine (1115C>G) instead of a cytosine. All seven other reported mutations are short frameshift deletions of 1, 2, 7, or 10 base pairs.4

SALL1 encodes four double zinc finger domains which are characteristically distributed over the entire protein.5 All known mutations have been predicted, if the mutated transcripts are indeed translated, to result in prematurely truncated proteins lacking all double zinc finger domains presumed to be essential for SALL1 gene function. Since no mutations were found 3′ of the most 5′ located double zinc finger encoding region, it was assumed that only those mutations which remove all double zinc fingers could cause TBS,4 whereas mutations located further 3′ in SALL1 could result in a different phenotype or no abnormal phenotype at all. Here we describe three novel mutations in three independent families illustrating that truncating mutations positioned further 3′ of the previously described hotspot region in SALL1also result in TBS.

All subjects available for investigations were examined forSALL1 mutations after giving informed consent, and all those available for investigations were clinically examined by a clinical geneticist. In all affected subjects …