ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22308078 Miller, et al., 2012 describe a daughter and father pair with features of TBS that both harbor a 149 kb deletion (chr16:49,625,560-49,802,988, hg18) encompassing only the SALL1 gene identified by high resolution SNP microarray. The grandmother and a great aunt on the paternal side also had features of TBS, but were not available for a formal clinical evaluation or FISH analysis.
16429401 Borozdin, et al, 2006 report three different heterozygous deletions found in three independent families with features of TBS. In the first family, a 75 kb deletion encompassing all exons of the SALL1 gene (portion of 5?UTR excluded) was paternally inherited in two affected siblings. While the father was reported to have some features of TBS, he was unavailable for formal clinical evaluation. A de novo 1.9-2.6 Mb deletion encompassing the SALL1 gene was found in an individual with asymmetric ears, dysmorphic thumbs, hearing loss, and a ventrally displaced anus with rectoperineal fistula at birth. Breakpoints were not provided for this deletion and therefore it is unclear whether additional genes are involved in this deletion. Furthermore, this patient was also found to have intellectual disability and speech delay. A proband with TBS features from a third family was found to carry an intragenic deletion of 3,384 bp that encompasses part of exon 2 and part of exon 3 of SALL1. Given that exon 1 remains intact it is possible that this deletion may create a truncated protein and exert a dominant negative effect similar to other SALL1 truncating variants located in exon 2 (see additional details in comments below).

Haploinsufficiency phenotype comments:

Townes Brock syndrome (TBS) is characterized by imperforate anus, thumb malformations and dysplastic ears with hearing loss, but phenotypic variability is often observed. Additional features may include for abnormalities heart defects and kidney issues. Evidence from mouse models and human cell lines demonstrate that TBS is caused by truncating variants in SALL1 that exert a dominant negative effect rather than haploinsufficiency (PMID: 29395072, 18000979, and 17895244). Human fibroblasts derived from TBS patients with truncating mutations in SALL1 show increased cilia formation and truncated SALL1 protein recruits full length SALL1 to the cytoplasm inappropriately (PMID: 29395072). This is consistent with previous studies showing truncated SALL1 mRNA transcripts escape nonsense mediated decay and instead interact with other proteins including full length SALL1 (PMID: 18000979 and 17895244). Additionally, while heterozygous and homozygous SALL1 knockout mice do not exhibit TBS features, mice harboring SALL1 truncating variants (found in humans) recapitulate the TBS phenotype found in humans (PMID: 11688560, 12915476 and 18470945). The two studies curated above are the only ones available that demonstrate possible haploinsufficiency as a cause of TBS. Additional studies have reported larger deletions extending beyond the SALL1 gene to be associated with a TBS-like phenotype (PMID: 20003547, 32037394, 25336016), however it is not clear whether adjacent genes play a role in the observed phenotypes. Taken together there is limited evidence supporting haploinsufficiency as a cause of TBS.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No literature identified.