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Townes-Brocks Syndrome

, MD
Center for Human Genetics
Freiburg, Germany

Initial Posting: ; Last Update: May 3, 2012.


Disease characteristics. Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (82%), dysplastic ears (88%) (overfolded superior helices and preauricular tags) frequently associated with sensorineural and/or conductive hearing impairment (65%), and thumb malformations (89%) (triphalangeal thumbs, duplication of the thumb (preaxial polydactyly), and rarely hypoplasia of the thumbs). Renal impairment (27%), including end-stage renal disease (ESRD) (42%), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%) (flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of cases. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation.

Diagnosis/testing. SALL1 is the only gene in which mutations are known to cause TBS. The diagnosis of TBS is based on clinical findings; detection of a SALL1 mutation confirms the diagnosis. Direct sequencing of the complete SALL1 coding region and quantitative real-time PCR analysis identify intragenic and larger deletions.

Management. Treatment of manifestations: Immediate surgical intervention for imperforate anus, surgery for severe malformations of the hands, routine management of congenital heart defects, hemodialysis and possibly kidney transplantation for ESRD, early treatment of hearing loss.

Surveillance: Regular monitoring of renal function in individuals with and without renal anomalies, even if renal function is normal on initial examination.

Genetic counseling. TBS is inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutations is estimated at 50%. Each child of an individual with TBS caused by a SALL1 mutation has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family.


Clinical Diagnosis

Townes-Brocks syndrome (TBS) is diagnosed clinically based on the presence of the following:

  • Imperforate anus
  • Dysplastic ears (overfolded superior helices, microtia)
  • Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without shortening of the radius

In the two most recent studies [Botzenhart et al 2005, Botzenhart et al 2007] of 61 persons with novel SALL1 mutations (not including the most common mutation, p.Arg276X [c.826C>T]), 84% had anal anomalies, 89% hand anomalies, and 87% ear anomalies; 67% had the characteristic triad.

In persons who show only two typical malformations, presence of additional anomalies commonly seen in TBS (e.g., renal malformations, hearing loss, heart defects) (see Clinical Description) can lead to the diagnosis.

Molecular Genetic Testing

Gene. SALL1 is the only gene in which mutations are known to cause Townes-Brocks syndrome.

Clinical testing

Sequence analysis/mutation scanning and deletion/duplication testing together identify a causative SALL1 mutation or deletion in approximately 70% of persons with the classic triad of malformations as described by Kohlhase et al [1999].

Table 1. Summary of Molecular Genetic Testing Used in Townes-Brocks Syndrome

Gene SymbolTest MethodsMutations DetectedMutation Detection Frequency by Gene and Test Method 1
SALL1Sequence analysis / mutation scanning Sequence variants 2<70%
Deletion / duplication analysis 3Exonic, multiexonic, or whole-gene deletions <5%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis in a proband with typical thumb, anal, and ear malformations

  • Perform cardiac evaluation, ophthalmologic examination, and renal ultrasound examination in addition to a routine physical examination.
  • Check for renal impairment by routine laboratory tests even if the kidneys appear normal on ultrasound.
  • Perform hand/forearm x-ray investigations to evaluate for involvement of the radius.
  • If at least two out of three classic major TBS features (anal, ear, and typical thumb malformations) are found, SALL1 molecular genetic testing is suggested as the first step.
    • Presence of additional minor features (i.e., those commonly observed in TBS) increases the likelihood of finding a SALL1 mutation.
    • Atypical features (i.e., not yet reported to occur with SALL1 mutations) may decrease the SALL1 mutation detection rate, but currently it does not seem possible to determine which atypical features (with the exception of concomitant involvement of the radius) are true negative predictors of a SALL1 mutation.
  • Molecular genetic testing of SALL4 rather than SALL1 is suggested as the first molecular test if the radius is involved and/or if Duane anomaly is present.
  • In a few individuals, complete overlap exists between Okihiro syndrome and TBS [Kohlhase et al 2002; Borozdin et al 2004; Kohlhase, personal communication]. In those individuals, both SALL1 and SALL4 molecular genetic testing should be considered. See Differential Diagnosis, Okihiro syndrome and SALL4-Related Disorders.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

In addition to the clinical features described in Diagnosis, the clinical manifestations of Townes-Brocks Syndrome may include the following:

  • Eyes. Microphthalmia (rare), iris coloboma, lamellar cataract, chorioretinal coloboma with loss of vision
  • Kidneys. Renal agenesis, renal hypoplasia, polycystic kidneys; functional impairment with or without structural abnormalities (42% of cases) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]
  • Hearing. Congenital sensorineural and/or conductive hearing loss ranging from mild to severe. Hearing loss that is mild may worsen with age (65% of cases).
  • Heart. Congenital heart disease occurs in 50% of persons with the common p.Arg276X mutation [Kohlhase et al 2003] and 12%-25% of persons with other SALL1 mutations [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]. Defects include atrial septal defect, ventricular septal defect, tetralogy of Fallot, lethal truncus arteriosus, pulmonary valve atresia, and persistent ductus arteriosus [Surka et al 2001].
  • Gastrointestinal. Anal stenosis, chronic constipation, gastroesophageal reflux [Engels et al 2000]
  • Face. Hemifacial microsomia [Kohlhase et al 1999, Keegan et al 2001]
  • Lower extremities. Club foot, overlapping toes (II and IV over III), syndactyly of toes, missing toes (III) (52% of cases) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]
  • Genitourinary. Hypospadias, vaginal aplasia with bifid uterus, bifid scrotum, cryptorchidism (36% of cases) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]
  • Central nervous system
    • Intellectual disability (~10%)
    • Behavioral problems, observed in many children with TBS [Kohlhase, unpublished observations]
    • Arnold-Chiari malformation type I [Kohlhase, unpublished observations]
    • Cranial nerve palsy (nerves VI and VII)
    • Duane anomaly. Uni- or bilateral limitation of abduction of the eye associated with retraction of the globe and narrowing of the palpebral fissure on adduction. The abducens nucleus and nerve (cranial nerve VI) are absent and the lateral rectus muscle is innervated by a branch of the oculomotor nerve (cranial nerve III), accounting for the aberrant ocular movements.
    • Hypoplasia of the dorsal part of corpus callosum
  • Skeletal. Rib anomalies (fused ribs, missing ribs, additional cervical ribs), mild vertebral anomalies (9% of cases). Painful joints have been observed in several adults with TBS [Kohlhase, unpublished observations.
  • Endocrine. Congenital hypothyroidism (rare)
  • Growth. Postnatal growth retardation. This poorly documented feature has been described in fewer than 6% to 29% of persons reported with TBS in the literature [Surka et al 2001]. The occurrence of postnatal growth retardation among mutation-positive individuals is not known.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been made for the majority of mutations, most of which are private.

The most common mutation and the only mutation found in more than two families is c.826C>T (p.276X), detected in approximately half of simplex cases with TBS (i.e., a single occurrence in a family) and in one familial case to date [Kohlhase et al 2003]. This mutation is associated with greater frequency (50%) and severity of congenital heart defects than other mutations. Fifteen of 16 heterozygotes for the mutation showed the characteristic triad of anal, thumb, and ear malformations (94%), indicating that the mutation is associated with a more severe phenotype.

In general, mutations within the hotspot region that is more 5' in exon 2 seem to be associated with a more severe outcome than mutations further 3' in exon 2. In addition, the phenotype associated with deletions of SALL1 seems to be milder than that associated with mutations in the hotspot region, but only three families with deletions have been reported to date [Borozdin et al 2006].


Penetrance seems complete, but expressivity is highly variable.


Apparent increased severity in successive generations is likely attributable to ascertainment bias.


Feichtiger [1943] provided one of the earliest reports of Townes-Brocks syndrome.

Townes & Brocks [1972] were the first to report autosomal dominant transmission of the characteristic anomalies.

Kurnit et al [1978] used the term REAR syndrome (for renal, ear, anal, and radial malformations).

Monteiro de Pina-Neto [1984] was the first to use the term Townes-Brocks syndrome.


The prevalence is unknown, partly because the clinical diagnosis of Townes-Brocks syndrome is often complicated by overlap with VACTERL association, which may lead to an over-ascertainment of TBS prevalence. Martinez-Frias estimated the prevalence at 1:250,000 but did not use stringent diagnostic criteria for TBS [Martinez-Frias et al 1999].

Differential Diagnosis

No other distinct phenotypes are associated with SALL1 mutations, but the clinical presentation of Townes-Brocks syndrome (TBS) can overlap with Goldenhar syndrome (hemifacial microsomia) [Gabrielli et al 1993, Kohlhase et al 1999, Keegan et al 2001], Okihiro syndrome (but without malformations of the radius) [Borozdin et al 2004], and branchiootorenal syndrome [Engels et al 2000, Albrecht et al 2004]. TBS also overlaps with VACTERL association.

Goldenhar syndrome.The majority of individuals with oculo-auriculo-vertebral spectrum phenotypes do not have upper-limb or anal malformations. However, some persons with SALL1 mutations have hemifacial microsomia. [Gabrielli et al 1993, Johnson et al 1996, Kohlhase et al 1999, Keegan et al 2001]. Therefore, while hemifacial microsomia alone is not suggestive of the presence of a SALL1 mutation, it may occur in individuals with a SALL1 mutation in addition to more typical TBS malformations.

Okihiro syndrome (Duane-radial ray syndrome) is characterized by Duane anomaly and radial ray defects, and less commonly by hearing loss and renal position anomalies (see SALL4-Related Disorders).

Branchiootorenal (BOR) syndrome. In two families eventually determined to have SALL1 mutations, no affected individual had the typical triad of thumb, anal, and ear malformations. Instead, the presence of dysplastic ears and renal malformations or impaired renal function in family members initially led to the consideration of BOR syndrome [Engels et al 2000, Albrecht et al 2004].

VACTERL association comprises vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal malformations, and limb defects. VACTERL is therefore an important differential diagnosis for simplex cases (i.e., a single affected individual in a family) with suspected TBS. To date, severe vertebral defects and tracheo-esophageal fistula have not been observed in persons with SALL1 mutations [Kohlhase, unpublished data]. Sib and offspring recurrence risks for VACTERL association are estimated at approximately 1%. A recent review summarizes current information on VACTERL association [Shaw-Smith 2006].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Townes-Brocks syndrome (TBS), the following evaluations are recommended:

  • Heart. Baseline evaluation by a cardiologist including an echocardiogram
  • Kidneys. Renal ultrasound examination and routine laboratory tests for renal function
  • Hearing. Hearing evaluation as soon as the diagnosis of TBS is suspected (see Deafness and Hereditary Hearing Loss Overview)

Treatment of Manifestations

  • Imperforate anus. Immediate surgical intervention is required.
  • Thumb malformations. Severe malformations of the hands may require surgery, e.g., removal of additional thumbs.
  • Heart defects. Severe congenital heart defects may require surgery if functionally relevant.
  • Renal. Function impairment requires continuous monitoring, hemodialysis, and possibly kidney transplantation.
  • Hearing loss. Significant impairment requires early treatment, mostly with hearing aids (see Deafness and Hereditary Hearing Loss Overview).


Renal function should be regularly monitored in all individuals with and without renal anomalies, even if no impairment of renal function is detected on initial examination.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Townes-Brocks syndrome (TBS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • About 50% of individuals diagnosed with TBS resulting from a SALL1 mutation have an affected parent; about 50% have the disorder as the result of a de novo mutation [Kohlhase, unpublished observation].
  • De novo SALL1 mutations most commonly occur (~ 87.5%) on the paternally derived chromosome 16 without an obvious age effect [Bohm et al 2006].
  • If a SALL1 disease-causing mutation cannot be detected in DNA extracted from the leukocytes of either parent, the two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Three cases of mosaicism including the germline have been reported [Kohlhase et al 1999, Blanck et al 2000, Devriendt et al 2002].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo SALL1 mutation include physical examination, examination of the limbs (x-rays of the forearms, inspection of the feet) and ears, a hearing test, ultrasound examination of the kidneys and laboratory tests for renal function, and heart examination. Clinical signs in parents with somatic mosaicism for a mutation may be as mild as toes II and IV overlapping the third toe [Devriendt et al 2002].

Note: Although about 50% of individuals diagnosed with Townes-Brocks syndrome have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband has a SALL1 mutation, the risk to the sibs of inheriting the mutation is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be about 1%-2% because of the possibility of germline mosaicism [Kohlhase, unpublished observation].

Offspring of a proband. Each child of an individual with Townes-Brocks syndrome has a 50% chance of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the genetic status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Fetus with high a priori risk. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Although this testing can determine whether or not the fetus has inherited the SALL1 disease-causing mutation, it cannot predict which manifestations will be present or their severity, with the exception of the p.Arg276X (c.826C>T) mutation, which has caused a severe phenotype in all known instances. High-resolution ultrasound examination is therefore recommended to evaluate the fetus for phenotypic manifestations. In a study of families with the mutation p.Arg276X, a fetus at risk was found to have a complex heart defect, preaxial polydactyly, foot malformations, and preauricular tags, suggesting TBS as the diagnosis [Kohlhase et al 2003].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Fetus with low a priori risk. If a fetus at no known increased risk for TBS has what appear to be features of classic TBS detected as early as the 16th week of pregnancy by a combination of high-resolution ultrasound and 3D ultrasound examinations, molecular genetic testing of SALL1 can confirm the diagnosis.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
  • Congenital Heart Information Network (CHIN)
    101 North Washington Avenue
    Suite 1A
    Margate City NJ 08402-1195
    Phone: 609-822-1572
    Fax: 609-822-1574
  • Medline Plus
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Townes-Brocks Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SALL116q12​.1Sal-like protein 1SALL1 homepage - Mendelian genesSALL1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Townes-Brocks Syndrome (View All in OMIM)

602218SAL-LIKE 1; SALL1

Normal allelic variants. SALL1 occupies about 14.1 kb (start codon to stop codon). It contains three exons (all coding) and two introns. The genomic sequence is available at (accession number NC_000016.8); 29 different non-pathogenic polymorphisms are currently known [Bohm et al 2006].

Pathologic allelic variants. All reported and confirmed mutations are truncating and positioned in exon 2 and intron 2 of the gene [Kohlhase et al 1998, Kohlhase et al 1999, Marlin et al 1999, Blanck et al 2000, Engels et al 2000, Kohlhase 2000, Salerno et al 2000, Surka et al 2001, Devriendt et al 2002, Kohlhase et al 2003, Walter et al 2006]. Forty-six out of the 56 known SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2.

Based on studies in mouse and chicken [Kiefer et al 2003, Sweetman et al 2003], it seems likely that the mutations escape nonsense-mediated messenger decay and therefore do not result in haploinsufficiency of the protein encoded by SALL1. However, three families in whom larger deletions partially or completely removing SALL1 clearly result in TBS have been described [Borozdin et al 2006]. One family had a heterozygous deletion of all exons, one had deletion of the entire SALL1 gene and several neighboring genes, and one had deletion of intron 2 and partial deletion of exons 2 and 3. These findings confirm that SALL1 haploinsufficiency can cause the phenotype, but it appears that the phenotype associated with larger deletions is at least milder than that of c.826C>T (though not milder than the phenotype associated with several other point mutations).

Normal gene product. SALL1 encodes a C2H2 zinc finger protein of the SAL type, similar to the SAL protein encoded by the Drosophila gene spalt. It contains four double zinc finger domains characteristically distributed over the protein. There are also two single zinc fingers, a C2HC domain at the N terminus and a C2H2 finger attached to the second double zinc finger. SALL1 is found strictly in the cell nucleus; it binds to heterochromatic foci and contains repressor domains at the N-terminus and in the central region [Netzer et al 2001, Netzer et al 2006]. Expression of csal1 (the chick orthologue of SALL1) in the limb is activated by ectopic SHH. However, this activation requires signals from the apical ectodermal ridge and involves FGF4/8 as well as Wnt3a and Wnt7a [Farrell & Munsterberg 2000], showing that csal1 expression is under control of at least three different pathways. In zebrafish, the SALL1 homologue sall1a is regulated by tbx5 and required for fgf10 and fgfr2 expression in the posterior pectoral fin bud [Harvey & Logan 2006]. In the mouse, Sall1 was found to enhance the canonical Wnt signaling pathway by localizing to pericentromeric heterochromatin [Sato et al 2004].

Abnormal gene product. All SALL1 mutations (except for the larger deletions) detected in persons with TBS to date result in premature stop codons. Since transcripts with a premature stop codon are in most instances rapidly degraded, these mutations are a priori likely to cause TBS via SALL1 haploinsufficiency [Hentze & Kulozik 1999, Maquat 2004]. Proof for SALL1 haploinsufficiency being involved in the pathogenesis of human TBS came from the recent detection of a heterozygous 75-kb deletion of the entire SALL1 coding region in a family with TBS [Borozdin et al 2006].

However, the Sall1 knock-out mouse showed that loss of Sall1 function does not result in defects that affect tissues other than kidney [Nishinakamura et al 2001]. Introducing a TBS mutation in mouse Sall1 instead leads to a TBS-like phenotype, and the detection of truncated Sall1 proteins points to a role of those proteins in the pathogenesis of TBS [Kiefer et al 2003]. In the zebrafish, sall1a loss of function leads to defective limb development, which can be aggravated by concomitant knock-down of sall4 [Harvey & Logan 2006].

Comparison of the phenotypes associated with a SALL1 deletion or with the severe p.Arg276X mutation indicate that the malformations in the family with the 75-kb deletion were relatively mild [Borozdin et al 2006]. It could therefore be that SALL1 deletions (i.e., SALL1 haploinsufficiency) cause milder phenotypes than truncating mutations. This would require that mutated SALL1 transcripts with premature stop codons escape the NMD pathway and lead to truncated proteins similar to those detected in mice with a TBS-causing mutation. However, truncated SALL1 proteins have not been found in lymphoblastoid and amniotic fluid cells of persons with TBS [Kohlhase & Rauchman, unpublished data], possibly because tissues most strongly expressing SALL1 in the adult (brain and kidney) have not been accessible for investigation.

Csal (chicken) and Sall (mouse) proteins can interact with each other via mediation of an N-terminal glutamine-rich domain conserved in all known Sal proteins. Expression of truncated Sall1/ csal1 proteins is detected throughout the cell and not confined to the nucleus as full-length Sall1. Truncated Sall1 can interact with full-length Sall proteins and cause their displacement from the nucleus [Kiefer et al 2003, Sweetman et al 2003].

Alleles resulting from SALL1 mutations in the 5' region of exon 2 encode for truncated proteins with strong repressor activity but without the central repression and heterochromatin localization domain [Netzer et al 2006]. Despite their potential to act as strong transcriptional repressors, these proteins will probably not localize to the physiologic site of action, but bind other SAL proteins and move them from the nucleus to the cytoplasm. Mutations further 3' in SALL1 likely result in milder phenotypes than the 5' mutations [Blanck et al 2000, Botzenhart et al 2005]. If some of those mutations lead to truncated proteins including both repression domains and the heterochromatin localization domain, these proteins could still localize to their place of action and have some residual function, which could explain the milder phenotype.

The critical point in the pathogenesis seems to be the correct dosage of functional SALL1 protein at the heterochromatic foci. A deletion of one allele results in a 50% reduction of this dosage. A 5' truncating mutation possibly leads to a truncated protein, which does not reach its site of action and in addition probably even removes some full-length protein of the normal allele from the nucleus. Therefore, in most instances the more severe phenotype of the 5' truncating mutations may result from a greater than 50% reduction of the functional protein at the site of action.

The additive phenotype of the combined sall4 and sall1a knock-down in zebrafish suggests that both genes may be able to compensate to some extent for each other. In view of the additive effects of sall1a and sall4 knock-down on limb development it remains unclear if the TBS phenotype in humans is only caused by loss of SALL1 function or also by an effect of the hypothetical truncated SALL1 proteins on the function of other SALL proteins.

As the interaction between truncated SALL1 and functional SALL1 or other SALL proteins and the relocalization of the functional proteins requires the presence of the evolutionarily conserved glutamine-rich region in the amino-terminal part of the truncated protein, the effect of the TBS-causing SALL1 mutations c.419delC and c.313delA, which would result in truncated proteins lacking the interaction domain, still needs to be explained, since the phenotypes associated with these mutations did not appear milder than the phenotypes resulting from other mutations [Kohlhase et al 1999, Botzenhart et al 2007].

Interestingly, 47 of 57 (82.5%) smaller mutations cluster within the 802-bp refined "hot spot region" between the coding sequence for the glutamine-rich domain and the coding sequence for the first double zinc finger, whereas only two mutations were found within the remaining 763 bp upstream in the coding region, and only six within the 2.4-kb coding region to the 3' end. Therefore, the existence of truncated proteins in cells of persons with TBS would not be surprising. If it holds true that SALL1 point mutations lead to truncated SALL1 proteins with dominant-negative action, one could expect that all truncated proteins have at least slightly different characteristics. This could explain the considerable phenotypic variability observed in TBS.


Literature Cited

  1. Albrecht B, Liebers M, Kohlhase J. Atypical phenotype and intrafamilial variability associated with a novel SALL1 mutation. Am J Med Genet A. 2004;125A:102–4. [PubMed: 14755477]
  2. Blanck C, Kohlhase J, Engels S, Burfeind P, Engel W, Bottani A, Patel MS, Kroes HY, Cobben JM. Three novel SALL1 mutations extend the mutational spectrum in Townes-Brocks syndrome. J Med Genet. 2000;37:303–7. [PMC free article: PMC1734570] [PubMed: 10819639]
  3. Bohm J, Munk-Schulenburg S, Felscher S, Kohlhase J. SALL1 mutations in sporadic Townes-Brocks syndrome are of predominantly paternal origin without obvious paternal age effect. Am J Med Genet A. 2006;140:1904–8. [PubMed: 16892410]
  4. Borozdin W, Steinmann K, Albrecht B, Bottani A, Devriendt K, Leipoldt M, Kohlhase J. 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. Hum Mutat. 2006;27:211–2. [PubMed: 16429401]
  5. Borozdin W, Wright M, Hennekam R, Hannibal M, Crow Y, Neumann T, Kohlhase J. Novel mutations in the gene SALL4 provide further evidence for Acro-Renal-Ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum. J Med Genet. 2004;41:e102. [PMC free article: PMC1735876] [PubMed: 15286162]
  6. Botzenhart EM, Bartalini G, Blair E, Brady AF, Elmslie F, Chong KL, Christy K, Torres-Martinez W, Danesino C, Deardorff MA, Fryns JP, Marlin S, Garcia-Minaur S, Hellenbroich Y, Hay BN, Penttinen M, Shashi V, Terhal P, Van Maldergem L, Whiteford ML, Zackai E, Kohlhase J. Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region. Hum Mutat. 2007;28:204–5. [PubMed: 17221874]
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Chapter Notes

Author Notes

Dr. Kohlhase’s Web site:


The author's research has received funding by the Deutsche Forschungsgemeinschaft (German National Science Foundation) and the Wilhelm-Sander-Stiftung, a German non-profit research foundation.

Revision History

  • 3 May 2012 (me) Comprehensive update posted live
  • 24 January 2007 (me) Review posted to live Web site
  • 17 November 2006 (jk) Original submission
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