Townes-Brocks syndrome: Detection of a SALL1 mutation hot spot and evidence for a position effect in one patient

Townes-Brocks syndrome (TBS) is an autosomal dominant developmental disorde r characterized by anal and thumb malformations and by ear anomalies that c an affect the three compartments and usually lead to hearing loss. The genr e underlying TRS, SALL1, is a human homolog of the Drosophila spalt gene wh ich encodes a transcription factor. A search for SALL1 mutations undertaken in 11 unrelated affected individuals (five familial and six sporadic cases ) led to the detection of mutations in nine of them. One nonsense and six d ifferent novel frameshift mutations, all located in the second exon, were i dentified. Together with the previously reported mutations [Kohlhase et al. , 1999], they establish that TBS results from haploinsufficiency. The findi ng of de novo mutations in the sporadic cases is consistent with the propos ed complete penetrance of the disease. Moreover, the occurrence of the same 826C>T transition in a CG dimer, in three sporadic cases from the present series and three sporadic cases from the other series [Kohlhase et al., 199 9] (i.e., six of the eight mutations identified in sporadic cases), reveals the existence of a mutation hotspot Six different SALL1 polymorphisms were identified in the course of the present study, three of which are clustere d in a particular region of the gene that encodes a stretch of serine resid ues. Finally, the chromosome 16 breakpoint of a t(5;16) (p15.3;q12.1) trans location carried by a TBS-affected individual was mapped at least 180 kb te lomeric to SALLI, thus indicating that a position effect underlies the dise ase in this individual. Hum Mutat 14:377-386, 1999, (C) 1999 Wiley-Liss, In c.