• Arg276X
• SALL1
• Townes–Brocks syndrome
• congenital heart defects

• TBS, Townes–Brocks syndrome

Townes–Brocks syndrome (TBS, OMIM #104780) is a rare autosomal dominant malformation syndrome characterised by anal, renal, limb, and ear anomalies.¹ TBS is caused by mutations in SALL1, a human putative zinc finger transcription factor gene related to the developmental regulator sal of Drosophila melanogaster.² The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved C2H2 double zinc finger domains that are evenly distributed. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif.³ The protein is exclusively found in the nucleus and localises to pericentromeric heterochromatin, acting as a transcriptional repressor.⁴

Twenty three of 24 SALL1 mutations known to date are located in exon 2.[2, 5–11 (and unpublished results)] These are short insertions and short deletions as well as one large intraexonic deletion, and nonsense mutations, one of which (c.826C→T, Arg276X) was found in seven independent families with sporadic TBS.^5–6,12 One mutation within intron 2 creates an aberrant splice site.⁷ All mutations lead to premature stop codons and have been thought to cause the phenotype via haploinsufficiency. However, neither heterozygous nor homozygous Sall1 knockout mice show the TBS phenotype, but homozygotes die from kidney malformations like those commonly seen in TBS,¹³ raising the possibility that SALL1 mutations in humans might have a dominant or dominant negative effect.

In a previous report, Marlin et al⁶ described the nucleotide 826C of the SALL1 cDNA as a mutational hotspot. They noted that the c.826C→T (Arg276X) mutation never occurred in a case of inherited TBS and speculated that this might be explained by infertility in carriers. In our cohort, we detected SALL1 mutations in 24 cases with sporadic TBS. Among these, …