Townes-Brocks Syndrome: Detection of a SALL1
Mutation Hot Spot and Evidence for a Position
Effect in One Patient
Sandrine Marlin,1 Stéphane Blanchard,1 Rima Slim,1 Didier Lacombe,2 Françoise Denoyelle,1,3
Jean-Louis Alessandri,4 Elisa Calzolari,5 Valérie Drouin-Garraud,6 F.G. Ferraz,7
Alain Fourmaintraux,8 Nicole Philip,9 Jean-Edmond Toublanc,10 and Christine Petit1*
1Unité de Génétique des Déficits Sensoriels, Institut Pasteur, Paris, France
2Pédiatrie & Génétique Médicale, Hôpital Pellegrin-Enfants, Bordeaux, France
3Service ORL, Hôpital d’Enfants Armand-Trousseau, Paris, France
4Service de Néonatologie, Hôpital Félix Guyon, St Denis, La Réunion
5Istituto di Genetica Medica, Universita degli Studi Ferrara, Ferrara, Italy
6Unité de Génétique Clinique, Hôpital Charles Nicolle, Rouen, France
7Department of Genetics, Pediatric Hospital D. Estefania, Lisbon, Portugal
8Unité de Néonatologie, Centre Hospitalier, St Pierre, La Réunion
9Centre de Génétique Médicale, Hôpital Timone-Enfants, Marseille, France
10Service Consultations, Hôpital Saint-Vincent de Paul, Paris, France
Communicated by Jean-Louis Mandel
Townes-Brocks syndrome (TBS) is an autosomal dominant developmental disorder characterized
by anal and thumb malformations and by ear anomalies that can affect the three compartments
and usually lead to hearing loss. The gene underlying TBS, SALL1, is a human homolog of the
Drosophila spalt gene which encodes a transcription factor. A search for SALL1 mutations under-
taken in 11 unrelated affected individuals (five familial and six sporadic cases) led to the detection
of mutations in nine of them. One nonsense and six different novel frameshift mutations, all
located in the second exon, were identified. Together with the previously reported mutations
[Kohlhase et al., 1999], they establish that TBS results from haploinsufficiency. The finding of de
novo mutations in the sporadic cases is consistent with the proposed complete penetrance of the
disease. Moreover, the occurrence of the same 826C>T transition in a CG dimer, in three spo-
radic cases from the present series and three sporadic cases from the other series [Kohlhase et al.,
1999] (i.e., six of the eight mutations identified in sporadic cases), reveals the existence of a
mutation hotspot. Six different SALL1 polymorphisms were identified in the course of the present
study, three of which are clustered in a particular region of the gene that encodes a stretch of
serine residues. Finally, the chromosome 16 breakpoint of a t(5;16)(p15.3;q12.1) translocation
carried by a TBS-affected individual was mapped at least 180 kb telomeric to SALL1, thus indicat-
ing that a position effect underlies the disease in this individual. Hum Mutat 14:377–386,
© 1999 Wiley-Liss, Inc.
KEY WORDS: Townes-Brocks syndrome; mutation; position effect
In 1972, Townes and Brocks  described a
syndrome comprising an imperforate anus, tri-
phalangeal thumbs, external ear anomalies (“satyr
ears”) and sensorineural deafness, and which showed
an autosomal dominant mode of transmission. The
prevalence of Townes-Brocks syndrome (TBS;
Received 27 May 1999; accepted revised manuscript 11 Au-
*Correspondence to: Christine Petit, Unité de Génétique des
Déficits Sensoriels, CNRS URA 1968, Institut Pasteur, 25 rue du
Dr Roux, 75724 Paris Cedex 15, France. E-mail: email@example.com
Grant sponsor: Association Française contre les Myopathies
Present address for Rima Slim: Department of Biochemistry,
American University, Beirut, Lebanon.
MIM# 107480) is unknown. To date, 113 cases have
been reported worldwide, 93 of which are familial;
the intrafamilial phenotypic expression is variable (for
review, see Allanson , and Marlin, in prepa-
ration). The typical clinical signs are malformations
of the anus (80% of the cases), radial axis (50% of
the cases, mainly preaxial polydactyly), and outer ear
(65% of the cases) which are often associated with
hearing loss (40% of the cases). The hearing loss can
be sensorineural, conductive, or mixed [Rossmiller
and Pasic, 1994]. Additional anomalies have been
reported [for review, see Powell and Michaelis, 1999],
namely, renal (19%) [Kurnit et al., 1978; Newman
et al., 1997], urogenital (15%) [de Vries-Van der
Weerd et al., 1988], skeletal (28%, mainly foot mal-
formations) [Green et al., 1996], and cardiac
(15%) [Barakat et al., 1988] anomalies. The di-
verse anomalies associated with TBS suggest a de-
velopmental defect taking place during the
organogenesis period, i.e., between embryonic weeks
5 and 10.
The gene responsible for TBS has been identi-
fied as SALL1 (MIM# 602218) by the detection
of a single basepair deletion and a nonsense muta-
tion in two affected families [Kohlhase et al., 1998].
SALL1 is one of two identified human homologs
[Kohlhase et al., 1996] of the Drosophila develop-
mental gene spalt which encodes a transcription
factor [Kühnlein et al., 1994]. Spalt mutants ex-
hibit homeotic head and tail transformations
[Jürgens, 1988]. Partial or complete cDNA se-
quences of spalt homologs from several species have
been characterized, namely msal-1 in mouse [Ott
et al., 1996], spalt in medaka fish [Köster et al.,
1997], and Xsal-1 in Xenopus [Hollemann et al.,
1996]. They encode proteins which contain the
typical eight amino acids “SAL-box” (FTTK-
GNLK) [Kühnlein et al., 1994] and a variable
number of zinc finger motifs.
Patients from 12 unrelated families (five familial
cases and seven sporadic cases) who upon careful
clinical examination were recognized as presenting
the most prominent features for TBS were studied.
We report on the molecular analysis of the SALL1
gene, which led us to detect the causative mutations
in nine of them. Moreover, the characterization of
the chromosome 16 breakpoint present in a TBS-
affected individual carrying a 5p16q translocation
allowed us to propose that a position effect is respon-
sible for the disease in this patient.
The diagnosis of TBS was based on the occur-
rence of anal and thumb malformations and ear
anomalies. Families TB3, TB4, TB5, TB8, TB11,
and TB10 [case report in Marlin et al., 1998] were
from France, TB1 and TB9 from Île de la Réunion
(Indian Ocean), TB2 from Spain, TB6 from Por-
tugal [case report in Ferraz et al., 1989], and TB7
from Italy [case report in Baldi et al., 1995]. Indi-
vidual TB12, carrying a t(5;16)(p15.3;q12.1) trans-
location, was described in Serville et al. .
Informed consent for the molecular analysis was
obtained from all families.
DNA was prepared from whole blood samples
by standard phenol/chloroform extraction and
ethanol precipitation. Molecular analysis was per-
formed in the propositus and both nonaffected
parents of families TB6, TB7, TB8, and TB9, in
the propositus and affected mother of families TB1,
TB3, and TB4, in the propositus and affected fa-
ther of family TB5, and only in the propositus of
families TB2, TB10, TB11, and TB12.
TABLE 1. Primers for PCR Amplification and Sequencing of the SALL1 Exons
Exon Forward (5′–3′) Reverse (5′–3′)
Primers located in introns and untranslated regions are in lower case, their positions are indicated in italics.
aSee primer sequences in Subjects and Methods.
bPrimers reported by Kohlhase et al. .
The PCR amplification and sequencing of double-
stranded DNA templates (dideoxy chain termina-
tor method using fluorescent dideoxynucleotides)
were performed under the same conditions as in Lévy
et al. . For exon 1 amplification, the primers
used were EX1a (starting in the noncoding part of
this exon, 32 bp 5′ from the ATG initiation codon)
and pEX1 (starting 143 bp 3′ from the donor splice
site of this exon) (Table 1). PCR amplification of exon
2 was carried out in two parts, using primer pairs TF1–
TR2 (5′ side, 1.5 kb amplicon) and TF2–TR5 (3′
side, 2.2 kb amplicon), and that of exon 3, using
primer pair TF5–TR5.1 according to Kohlhase et al.
. The primers used for sequencing are listed
in Table 1.
In patient TB5, PCR amplification using primers
TF2 (within exon 2) and TR5 (within intron 2) re-
sulted in the normal 2.2 kb band and an additional
1.1 kb band. The latter was separated from the nor-
mal one by agarose gel electrophoresis and sequenced.
Ten µg of HindIII-digested genomic DNA were
run on a 0.8% agarose gel and blotted onto N+-
Hybond filters (Amersham, Arlington Hts., IL). Blots
were hybridized in Church buffer overnight at 65°C.
Membranes were washed in 0.2x SSC, 0.1% SDS at
65°C. The probes used to analyze each of the SALL1
exons were derived by PCR amplification using the
primer pairs EX1A–pEX1 for exon 1 (see above),
TF1–TR5 or TF2–TR5 for exon 2, and TF5–TR5.1
for exon 3 [Kohlhase et al., 1998].
DNA from P1 phage artificial chromosome
(PAC) 4645 and yeast artificial chromosome
(YAC) 438H5 was partially digested with Sau 3AI,
and run on a 0.6% agarose gel. Fragments in the
15–20 kb range were eluted, ligated to λ pGEM11
vector (Promega, Madison, WI), and packaged in
E. coli KW251 using the Promega Packaging sys-
tem extract. To construct a contig of λ clones cov-
ering PAC 4645 and YAC 438H5, the extremities
of this PAC, this YAC, and each subsequently se-
lected λ subclone were sequenced and used as
probes (after PCR amplification) to get overlap-
ping new λ clones from the library. The clones
covering the entire PAC 4645 and the telomeric
100 kb of YAC 438H5 were sequenced.
Pedigrees of the five families affected by TBS. The propositus is indicated by an asterisk.
TABLE 2. Summary of the Clinical Features Presented by the TBS Patients
Bilateral renal hypoplasia
Persistent ductus arteriosus
Foot malformations + abnormal toes
Normal renal ultrasonography
Normal renal ultrasonography
TB2 (F)ImperforateTriphalangeal thumbs Preauricular tagsMixed
TB3 (F) Imperforate
Broad thumbs Microtia
Low set ears
Low set ears
TB5 (F) Bifid thumbsUnknown Unilateral renal agenesis
Normal renal ultrasonography
Ventricular septal defect
Bilateral renal hypoplasia
TB6b (S) Imperforate
TB7c (S) Imperforate
External auditory atresia
Preauricular tags + pits
External auditory atresia
TB8 (S)Imperforate Hexadactyly
Normal renal ultrasonography
Normal renal ultrasonography
Normal renal ultrasonography
Hand + foot syndactylies
Normal renal ultrasonography
TB11 (S) Imperforate NoExternal ear aplasiaMixed
Triphalangeal thumbsPreauricular tags
aF = familial case; S = sporadic case.
bThe mutation identified in this patient [described in Ferraz et al., 1989], was not detected in either of her parents, thus leading to the conclusion that the
deafness and other mild symptoms affecting the grandfather (and his own grandfather and granduncle) [see pedigree in Ferraz et al., 1989] cannot be ascribed
cDescribed in Baldi et al. .
dA mutation in the gene coding for the C1 inhibitor has been identified in this individual and other family members who suffered from angioedema [Verpy et
al., 1996]; none of the latter presented with TBS anomalies.
eDescribed in Marlin et al. .
fDescribed in Serville et al. . This patient carries a t(5;16)(p15.3;q12.1) chromosomal translocation.
Metaphase chromosome spreads from individual
TB12 (t(5;16)(p15.3;q12.1)) were prepared and
hybridized, as described previously [Vincent et al.,
1994], with probes corresponding to the entire
YAC 438H5, the entire PAC 4645, and each of its
The cDNA sequence corresponding to SALL1
first exon, obtained as a result of 5′ RACE-PCR (not
shown) (GenBank accession number AF074949),
and the genomic structure that we established in
parallel were entirely consistent with those reported
in the meantime [Kohlhase et al., 1999] (GenBank
accession number Y18265). Eleven unrelated indi-
viduals affected by TBS, without any detectable
karyotypic anomaly, were studied. They consist of
five familial (families TB1 to TB5, pedigrees in Fig.
1) and six sporadic (individuals TB6 to TB11) cases.
The clinical features of the patients are described in
Table 2 and Figure 1. The three SALL1 coding ex-
ons were PCR-amplified and sequenced in the
proband and in both parents whenever possible. For
that purpose, specific primer pairs were designed for
the first two exons (see Table 1), whereas the previ-
ously described primers were used to explore the third
exon [Kohlhase et al., 1998]. Mutations were iden-
tified in nine patients. They consist of seven differ-
ent mutations: one nonsense mutation, three
microdeletions, two microinsertions, and one large
complex deletion (Table 3a, and see Figs. 2 and 3).
All are located in the second exon and result in pre-
mature protein truncation. No SALL1 mutation was
detected in patients TB10 and TB11; Southern blot
analysis, using probes corresponding to each of the
three SALL1 exons, failed to detect any gross DNA
rearrangement in these patients either (see Fig. 3;
and data not shown).
In addition to the aforementioned mutations,
six nucleotide changes were identified, of which
two are silent polymorphisms, two lead to an
amino acid change (S159G, G1265E), and two
result in the insertion (S149-150ins) or dele-
tion (S164del) of a serine residue (Table 3b).
The latter four mutations were considered as
asymptomatic polymorphisms since three of
them were present in both the propositus and
an unaffected parent or relative, and the re-
maining one (S149-150ins, in family TB4) was
present simultaneously with the 1565delC
frameshift mutation (Table 3a), supposed to be
responsible for the disease in this family.
The occurrence of a balanced translocation
t(5;16)(p15.3;q12.1) in a TBS-affected child
(TB12) has permitted the assignment of the caus-
ative gene to 16q12.1 [Serville et al., 1993]. No
SALL1 modification was detected in TB12, either
by DNA sequencing or by Southern blot analysis
(Fig. 3). A PAC library and a YAC library were
screened with sequence tagged sites (STSs) of the
paracentromeric region of chromosome 16. The
clones so selected were characterized by FISH on
the patient’s chromosomes. We thereby identified
PAC 4645, encompassing the 16q breakpoint, and
YAC 438H5 (180 kb, located centromeric to the
breakpoint) (not shown). PAC 4645 (Fig. 4a) was
subcloned into λ phages which were ordered into
a contig (see Subjects and Methods). The λ 12.6
subclone spanning the breakpoint was identified
by FISH (Fig. 4b). According to the contig map, λ
12.6 was located at approximately 40 kb from the
centromeric end of PAC 4645. Since sequencing
of this PAC as well as PCR amplification of the
TABLE 3. Nucleotide Changes in SALL1 and Predicted
Modifications of the Protein
TB6, TB7, TB8 (S)
(a) Mutations in TBS affected patients.
*F = familial, S = sporadic.
In patient TB5, PCR amplification of the 3′ part of exon 2
revealed a band of the expected size (2.2 kb), and a smaller
additional band (1.1 kb) which was sequenced (not shown).
This allowed us to identify a 1.1 kb complex deletion within
which a short segment of 6 bp was preserved. This deletion
predicts the loss of a HindIII restriction site in exon 2 which
was performed by Southern blot analysis (see Fig. 3).
**These nucleotide changes have also been reported in
Kohlhase et al. . Nomenclature according to Beaudet
and Tsui  modified by Antonarakis .
adjacent YAC 438H5 failed to detect any SALL1
sequence within this interval, we undertook a
physical mapping of this chromosomal region. We
first selected a bacterial artificial chromosome
(BAC 230e15) containing the three SALL1 ex-
ons. The distal end of YAC 438H5 was found to
overlap approximately 30 kb of PAC 4645, and its
proximal end about 10 kb of BAC 230e15 (Fig. 4a;
graph (wt) is presented in parallel. For three mutations, the sequence of the DNA strand which is presented is complemen-
tary to that of the cDNA, and the direct sequence has been added on top of the normal electrophoretogram.
Electrophoretograms showing the mutations in six TBS individuals. In each case, the corresponding normal
see Subjects and Methods). These results show that
the chromosomal breakpoint in TB12 is located
at a minimal distance of 180 kb from SALL1. The
present data establish that TBS in this patient re-
sults from a position effect [for review, see Kleinjan
and van Heyningen 1998], the mechanism of
which awaits further characterization. In particu-
lar, in the absence so far of characterization of the
SALL1 regulatory elements, the disruption of a
remote one should be considered.
In this series, the causative mutations or chro-
mosomal rearrangement were detected in 10 out
of 12 unrelated TBS-affected individuals. No
SALL1 mutation or karyotypic anomaly was de-
tected in patients TB10 and TB11. The possibility
of a misdiagnosis for these patients seems unlikely,
as they both present with classical clinical features
of TBS (see Table 2). As there is no evidence for
genetic heterogeneity in TBS, TB10, and TB11
presumably carry a mutation in the unexplored
regions of SALL1, i.e., the promoter, introns, and
5′ and 3′ untranslated regions. Alternatively, TBS
in these patients might result from a position ef-
fect associated with a chromosomal rearrangement
undetected by the karyotypic analysis.
None of the four mutations identified in the
sporadic cases (TB6, TB7, TB8, and TB9) was
detected in either of the parents, demonstrating
that these mutations occurred de novo. Together
with the four de novo mutations from the other
series [Kohlhase et al., 1998, 1999], the present
results bring the total number of de novo muta-
tions to 8 out of 20 identified SALL1 mutations.
Assuming the absence of a recruitment bias in the
two series of patients, this indicates that a high
proportion of TBS cases are due to de novo muta-
tions. The finding of de novo mutations in spo-
radic cases is consistent with the proposed full
penetrance of the disease [Arroyo Carrera et al.,
1996]. So far, only one phenotypically normal in-
dividual was found to carry a SALL1 mutation. In
this case, however, the likely mosaic state of the
mutation would account for the absence of TBS
features [Kohlhase et al., 1999].
The six novel SALL1 mutations from the
present study together with the seven reported by
Kohlhase et al. [1998, 1999], make a total of 15
different identified mutations in TBS. All are lo-
cated in the second exon (see Fig. 5) and predicted
to lead to a truncated protein. So far, only one
mutation, namely the C to T transition at posi-
tion 826, has been detected in several unrelated
patients (Table 3a, Fig. 5). In the present series,
this mutation was detected in three out of four
sporadic cases with identified SALL1 mutations.
The same mutation has been observed in three out
of four sporadic cases with identified mutations in
the other series [Kohlhase et al., 1999]. The 826-
827CG dimer where this transition occurs thus
represents a hotspot of mutations that can be at-
tributed to uncorrected spontaneous deamination
of a methylcytosine [Duncan and Miller, 1980].
This mechanism has been proposed to represent
the most frequent source of mutations in humans
[Barker et al., 1984]. It is noteworthy that the
826C>T nonsense mutation, which largely ac-
counts for the observed high proportion of de novo
mutations in TBS, has never been found in famil-
ial cases. It is therefore tempting to speculate that
this particular mutation does not allow fertility.
This hypothesis could not be put to the test so far
because the three affected females of the present
individuals. HindIII-digested genomic DNA from BAC
230e15 (lane 1), patients TB12 (t(5;16)(p15.3;q12.1))
(lane 2), TB10 (lane 3) and TB11 (lane 6) (two sporadic
TBS cases with no detected point mutation), TB5 (1.1 kb
deletion) (lane 4), and one control individual (lane 5) were
hybridized with a PCR product obtained using primers
TF2–TR5, corresponding to the 3′ part of exon 2 (see
Subjects and Methods). This probe detects two SALL1
specific bands (2.5 kb and 3 kb) in all individuals except
TB5 (lane 4), who carries a heterozygous 1.1 kb deletion
which results in the loss of an HindIII restriction site and
gives rise to the additional 4 kb band. The two other bands
detected by this probe are indicative of a yet-unidentified
SAL gene or pseudogene.
Southern blot analysis of SALL1 exon 2 in TBS
230e15 contains the entire SALL1 coding sequence. The 3′–5′ orientation of SALL1 with regard to YAC 438H5 (180 kb)
was not determined. PAC 4645 encompasses the translocation breakpoint in patient TB12. B: FISH analysis of individual
TB12 carrying the t(5;16)(p15.3;q12.1) translocation. Metaphase chromosome spreads were hybridized with a probe
derived from the λ 12.6 subclone of PAC 4645 (see A). A signal is detected on the normal chromosome 16 and on both
the der5 and der16 translocated chromosomes.
Analysis of the breakpoint present in a TBS-affected individual. A: Physical map of the TBS region. BAC
study are still too young and the age of the three
affected males from the report by Kohlhase et al.
 was not mentioned.
Among the six sequence polymorphisms iden-
tified in the present study, three, namely S159G,
S149-150ins, and S164del, deserve further com-
ment. These polymorphisms are located in a par-
ticular region of SALL1 (amino acid residues 150
to 166) which is characterized by a stretch of 10
serine residues, encoded by an (AGC)10 repeat,
followed by four glycine residues encoded by a
(GGC)4 repeat and three serine residues, the first
of which (S164) is also encoded by an AGC codon.
The S159G mutation is located at the last posi-
tion of the stretch of 10 serine residues, S149-
150ins is located in the same stretch of serine
residues, and S164del involves the serine immedi-
ately following the glycine repeat. These mutations
define a particularly unstable region prone to DNA
modifications, most of which are likely to result
from DNA polymerase slippage. Such a mecha-
nism would also account for the S150del polymor-
phism reported by Kohlhase et al. .
All the mutations detected so far [Kohlhase et
al., 1998, 1999; this study] indicate that TBS re-
sults from SALL1 haploinsufficiency. This syn-
drome is to be added to the long list of dominant
developmental diseases that are caused by
haploinsufficiency of a gene encoding a transcrip-
tion factor, such as aniridia (PAX6 [Fantes et al.,
1995]), Waardenburg syndrome types I and II
(PAX3 and MITF, respectively [reviewed in Read
and Newton, 1997]), Pallister-Hall and Greig syn-
dromes (GLI3 [Kang et al., 1997]), a form of Rieger
syndrome (RIEG [Flomen et al., 1998]). In such
diseases, different threshold levels of the protein
are believed to be critical for each of the associ-
ated developmental processes, which likely ac-
counts for the variable phenotypic expressivity [for
review, see Fisher and Scambler, 1994]. Accord-
ingly, considerable variability of the clinical fea-
tures was noted among the TBS-affected patients
in our series (see Table 2), even within a given fam-
ily (see Fig. 1).
The molecular diagnosis of TBS by direct se-
quencing on genomic DNA is simple, as there are
only three SALL1 coding exons to be analyzed, and
it allows the detection of a high proportion of the
mutations (i.e., in 9 out of 11 patients analyzed in
the present study). This test should prove poten-
tially helpful in medical practice since the clinical
features of TBS are sometimes difficult to distin-
guish from those of other syndromes [for reviews,
see Kotzot et al., 1992; Allanson, 1995] (Marlin,
unpublished observations); in particular, the
VACTERL association (MIM# 192350) [Khoury
et al., 1983]. In addition, the present character-
ization of a normal SALL1 coding sequence in a
TBS patient carrying a 16q12 chromosomal rear-
rangement indicates performing a karyotype, in
case a typical TBS with no SALL1 mutation is iden-
tified. An improvement in genetic counseling for
TBS-affected families is expected from these ge-
We thank the families for participation in this
study. We thank Dominique Weil for helpful ad-
vice, Michel Salmon for preliminary physical map-
ping, Jean-Pierre Hardelin, Viki Kalatzis, and
Jacqueline Levilliers for contributions to the writ-
ing and for critical reading of the manuscript, and
Ana Baroncini (Ferrara) for clinical examination
of patient TB7. The technical assistance of
Fabienne Levi-Acobas in subcloning and of
Stéphane Douglay in sequencing is acknowledged.
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The protein comprises five zinc finger domains (dotted rectangles), including a “vertebrate-specific” C2HC motif, three
double C2H2 motifs, plus an additional one [Kohlhase et al., 1996]. The stretch of serine residues (aa 150–166) is
indicated by a stippled rectangle. The two exon–intron limits are indicated by gray triangles. The sites of the mutations so
far identified in TBS patients are indicated by arrows. The 826C>T transition has been detected in six sporadic cases
(three from each series) and therefore represents a mutation hot spot.
Schematic representation of the human SALL1 protein and localization of the mutations identified thus far.
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