Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome.
Taken together, they do not support the correlation of SALL1 deletions with a milder TBS phenotype and highlight a need for more robust clinical phenotyping combined with investigation of mutational mechanism.
Furthermore, the Hsal 1 gene product may play a part in the pathogenesis of specific neoplasms occurring in these organs in addition to its specific role in Townes-Brocks syndrome.
The SALL1 gene has been associated with the Townes-Brocks Syndrome (TBS), a disorder characterized by multiorgan dysgenesis including renal and genital malformations.
Human SALL1 is a homologue of the Drosophila region-specific homeotic gene sal, and is also known as a causative gene for Townes-Brocks syndrome, which is characterized by multi-organ malformations.
In SALL1, a mutant allele causing Townes-Brocks syndrome was unexpectedly resistant to NMD, whereas a different mutation causing a much milder phenotype was susceptible to NMD.
Finally, the chromosome 16 breakpoint of a t(5;16)(p15.3;q12.1) translocation carried by a TBS-affected individual was mapped at least 180 kb telomeric to SALL1, thus indicating that a position effect underlies the disease in this individual.
We hypothesize that interactions of SHH and SALL1 explain the overlapping features of the family described here and patients with Townes-Brocks syndrome.