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Background: All previous genetic testing has failed to identify the genetic cause of syndrome affecting this family for nearly 20 years. The advent of massively parallel next-generation sequencing technologies has provided an opportunity to affordably screen exomes to establish the genetic basis of disease. The utility of whole exome sequencing to identify causative variants of Mendelian disorders has been clearly demonstrated in the research arena. In this report, we describe a family with unique clinical features, including Hirschsprung disease, with a suspected genetic basis. Methods: We employed whole exome sequencing to this case to identify causative mutations. Results: We identified two novel compound heterozygous variants, following an autosomal recessive mode of inheritance, in the candidate gene SALL1, a gene known to cause Townes-Brocks syndrome (TBS) and central nervous system TBS (CNS-TBS). The pathogenicity of the two variants was supported by co-segregation, low frequency, location in mutation hotspot, pathogenicity program predictions, phenotype similarity, and immunohistochemical staining. As previously reported, we observed intrafamilial phenotypic variability among the affected individuals and they may represent an expansion of TBS, CNS-TBS or a new CNS-TBS-like syndrome by observing atypical features in affected individuals including mental retardation, developmental delay, tracheal anomalies, Hirschsprung disease and cleft lip and palate. Conclusion: Solving this case brought a new view of the genetics of TBS and its relationship with SALL1. Another lesson learned is that advanced technologies have a profound impact on old, unsolved cases such as the one presented here. Thus, we further demonstrated the utility of exome sequencing in the research arena.

Two Novel Mutations in SALL1 Cause Townes-Brocks-Like Syndrome: New Findings from an Old Case