Townes-Brocks Syndrome via the SALL1 Gene

Townes-Brocks syndrome (TBS, OMIM#107480) is a multiple malformation syndrome characterized by the triad of imperforate anus, dysplastic ears frequently associated with sensorineural or conductive hearing impairment, and thumb malformations (triphalangeal thumbs, preaxial polydactyly, hypoplastic thumbs) without shortening of the radius. Foot malformations (flat feet, overlapping toes) and genitourinary malformations are also common. Renal impairment including end-stage renal disease, congenital heart disease, and mental retardation may occur (Kohlhase. GeneReviews. 2007).

Townes-Brocks syndrome (TBS) is inherited in an autosomal dominant manner. Penetrance seems complete, but expressivity is highly variable. SALL1 is the only gene known to be associated with TBS; about half of cases are caused by de novo variants. SALL1 encodes sal-like protein 1, a C2H2 zinc finger transcription factor of the SAL type. Sal-like protein 1 appears to be an essential developmental regulator, which interacts with SALL4 and is regulated by TBX5 (Harvey&Logan Development 133:1165–1173, 2006). The majority of reported variants in SALL1 are nonsense and frameshift variants that positioned in exon 2 of the gene and resulted in premature stop codons. Both haploinsufficiency and dominant-negative effects of mutated SALL1 protein have been proposed for the pathogenesis of TBS (Kohlhase GeneReviews 2007; Maquat et al. Nat Rev Mol Cell Biol 5:89–99, 2004; Borozdin et al. Hum Mutat 27:211–212, 2006; Kiefer et al. Hum Mol Genet. 12:2221–2227, 2003).

Sequencing of SALL1 is predicted to detect disease variants in up to 70% of individuals with the classic triad of malformations (Kohlhase GeneReviews 2007; Kohlhase et al. Am J Hum Genet 64:435-445, 1999; Marlin et al. Hum Mutat 14:377-386, 1999). Large deletions involving single or multiple exons have been reported to account for less than 5% cases (Borozdin et al. Hum Mutat 27:211-212, 2006); such deletions are generally not detected by sequence analysis.

This test provides full coverage of all coding exons of the SALL1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).