SALL1 – Townes-Brocks Syndrome

Townes-Brocks syndrome (TBS) is an autosomal dominant congenital malformation syndrome characterized by the triad of imperforate anus, dysplastic external ears, and thumb anomalies. Mutations in SALL1 (HGNC:10524) on chromosome 16q12.1 cause TBS (PMID:9973281), with disease‐defining features including ear malformations, anal atresia, and triphalangeal thumbs (HP:0000356, HP:0002023, HP:0001199).

Genetic evidence includes over 56 distinct truncating variants identified in at least 23 unrelated families, with recurrent hotspot mutation c.826C>T (p.Arg276Ter) observed in six sporadic and three familial cases (PMID:17221874). The inheritance is autosomal dominant, with segregation of pathogenic SALL1 alleles in multi‐generation pedigrees, involving at least 19 additional affected relatives (PMID:20520617). Most variants are nonsense or frameshift changes predicted to escape nonsense‐mediated decay and act via a dominant‐negative mechanism.

Variant spectrum is dominated by exon 2 truncations: c.826C>T (p.Arg276Ter) recurs in multiple populations; short deletions such as c.878_887del (p.Leu293GlnfsTer18) and duplications like c.469_512dup (p.Ile172fs) further define the mutational hotspot (PMID:10533063). In contrast, rare SALL1 deletions lead to milder phenotypes through haploinsufficiency (e.g., 75 kb–2.6 Mb deletions), underscoring dosage sensitivity (PMID:16429401).

Functional studies demonstrate that wild-type SALL1 encodes a zinc-finger transcriptional repressor that localizes to pericentromeric heterochromatin and interacts with TRF1/PIN2 (PMID:11751684). Expression of truncated Sall1 in a mouse knock‐in model recapitulates TBS features—renal hypodysplasia, anal and limb deformities—supporting a dominant‐negative pathogenesis (PMID:12915476).

While most point mutations exert dominant‐negative effects, SALL1 deletions causing haploinsufficiency yield a milder TBS spectrum, indicating variable expressivity and partial functional compensation (PMID:16429401). No studies to date refute the SALL1–TBS association.

Collectively, the SALL1–Townes-Brocks syndrome relationship is classified as Definitive based on robust segregation, a broad variant spectrum in >56 probands, and concordant functional data. Genetic testing of SALL1 should be prioritized for individuals with the characteristic TBS triad to enable accurate diagnosis, genetic counseling, and management.

References

• American Journal of Human Genetics • 1999 • Molecular analysis of SALL1 mutations in Townes-Brocks syndrome. PMID:9973281
• Human Mutation • 1999 • Townes-Brocks syndrome: detection of a SALL1 mutation hot spot and evidence for a position effect in one patient. PMID:10533063
• Human Molecular Genetics • 2003 • Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects. PMID:12915476
• Human Mutation • 2007 • Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region. PMID:17221874
• European Journal of Medical Genetics • 2009 • Phenotypic variability in a family with Townes-Brocks syndrome. PMID:20520617
• Human Mutation • 2006 • Detection of heterozygous SALL1 deletions by quantitative real time PCR proves the contribution of a SALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome. PMID:16429401

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