🏷

Classifications

Harrison's Part

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal dominant HP:0000006

Heterozygous SALL1 pathogenic variants are transmitted in an autosomal dominant manner with a 50% risk to each child of an affected individual. About half of probands carry a de novo variant, and de novo variants arise predominantly on the paternally derived chromosome 16 without an obvious paternal age effect. Expressivity is highly variable within and between families; mildly affected parents are often recognized only after a more severely affected child, which is one reason for testing apparently unaffected at-risk relatives. Penetrance is usually described as complete, but a Chinese hearing-loss cohort reported apparently incomplete penetrance in the transmitting generation of several families.

Autosomal dominant inheritance Expressivity: VARIABLE De novo rate: About 50% of individuals diagnosed with SALL1-TBS

Show evidence (5 references)

PMID:20301618 SUPPORT Human Clinical

"SALL1-TBS is inherited in an autosomal dominant manner. About 50% of individuals diagnosed with SALL1-TBS have the disorder as the result of a de novo pathogenic variant."

GeneReviews states the inheritance pattern and the de novo fraction.

PMID:20301618 SUPPORT Human Clinical

"Each child of an individual with SALL1-TBS has a 50% chance of inheriting the pathogenic variant."

GeneReviews states the 50% transmission risk to each child of an affected individual.

PMID:16892410 SUPPORT Human Clinical

"Mutations were of paternal origin in 14 of 16 cases (87.5%). Paternal origin was independent of the mutation type."

Parent-of-origin analysis in 16 sporadic families shows de novo SALL1 variants arise mostly on the paternal allele.

+ 2 more references

◈

Mechanistic Hypotheses

1

Truncated SALL1 causes TBS malformations partly through primary cilium dysfunction

tbs_truncated_sall1_ciliary_dysfunction EMERGING

Evidence balance 1 support

Cytoplasmic truncated SALL1 binds CCP110 and CEP97 and destabilizes LUZP1, increasing ciliogenesis and altering Sonic hedgehog transduction; the hypothesis is that this transcription-independent activity contributes to the limb and other malformations. Supported by patient fibroblasts and model cell lines; not tested in vivo.

Pathograph links

Truncated SALL1 Protein Escaping Nonsense-Mediated Decay -> Aberrant Primary Cilium Formation DIRECT Cytoplasmic truncated SALL1 binds the ciliogenesis suppressors CCP110 and CEP97, a function independent of transcriptional repression.

Aberrant Primary Cilium Formation -> Disrupted Autopod Digit Patterning INDIRECT UNKNOWN INTERMEDIATES Proposed rather than demonstrated: altered ciliary Hedgehog transduction would perturb limb patterning, which depends on Sonic hedgehog signalling.

Show evidence (1 reference)

PMID:29395072 SUPPORT In Vitro

"Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity."

States the hypothesis tested in cellular models.

?

Discussions and Knowledge Gaps

2

Why do humans with a heterozygous SALL1 deletion have Townes-Brocks syndrome when heterozygous Sall1-null mice have no TBS-like phenotype?

HUMAN MODEL MISMATCH mismatch_sall1_null_heterozygote

Attached to

pathophysiology#SALL1 Haploinsufficiency pathophysiology#Dominant-Negative Interference with SALL-Family Repressors

The dominant-negative model rests largely on the contrast between the mouse null allele (no phenotype in heterozygotes) and the mouse truncating allele (TBS-like heterozygotes). Human deletion carriers show that halving SALL1 dosage is itself pathogenic in humans, so the mouse overstates how cleanly the two mechanisms separate. Whether human deletion carriers are genuinely milder is also disputed on few families. Until this is resolved the entry carries both mechanisms as PROVISIONAL.

Proposed experiments

Isogenic human iPSC SALL1 allelic series in kidney organoids

exp_sall1_isogenic_ipsc_allelic_series

Compare heterozygous SALL1 deletion, hotspot truncating (p.Arg276Ter) and wild-type isogenic iPSC lines differentiated into kidney organoids for nephron progenitor maintenance and nephron number, testing in human cells whether a truncating allele is more damaging than a null allele.

Standardized phenotyping of SALL1 deletion carriers

exp_sall1_deletion_phenotype_registry

Collect uniformly phenotyped deletion carriers (renal imaging, audiology, cardiac and developmental assessment) and compare against age-matched hotspot-variant carriers to settle the milder-phenotype question.

What causes chronic kidney disease in TBS patients whose kidneys appear structurally normal on ultrasound?

KNOWLEDGE GAP gap_ckd_structurally_normal_kidneys

Attached to

phenotypes#Chronic Kidney Disease pathophysiology#Impaired Metanephric Kidney Development

Most TBS kidney failure is attributed to congenital hypodysplasia, but kidney failure without an ultrasound abnormality is reported and FSGS has been found on biopsy. Reduced nephron endowment below the resolution of ultrasound, a role for SALL1 in the mature kidney (Sall1 is expressed in terminally differentiated renal epithelia in adult mouse), or both are possible. The answer determines whether kidney surveillance could be tailored by imaging or must remain universal.

Proposed experiments

Nephron number estimation in TBS patients with normal kidney ultrasound

exp_sall1_nephron_number_imaging

Estimate nephron number (e.g. MRI-based or biopsy-based methods) and follow eGFR and proteinuria longitudinally in molecularly confirmed patients without structural anomalies.

⚙

Pathophysiology

9

SALL1 Truncating Variant

A heterozygous germline nonsense or frameshift SALL1 variant, clustering in an ~800 bp hotspot in exon 2 between the glutamine-rich domain and the first double zinc-finger domain. The predicted product is a truncated protein that retains the N-terminal repression and SALL-interaction regions but lacks the C-terminal DNA-binding double zinc fingers. The recurrent c.826C>T (p.Arg276Ter) accounts for roughly half of simplex cases and has been associated with a more complete phenotype, including congenital heart defects.

SALL1 hgnc:10524

Genetic context SALL1 hgnc:10524 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Truncating alleles that escape nonsense-mediated decay and are thought to act through the truncated product rather than by loss of one allele. The dominant-negative assignment rests on mouse genetics and patient-cell work (see downstream nodes); ClinGen records the mechanism as either haploinsufficiency or dominant-negative.

Downstream

Truncated SALL1 Protein Escaping Nonsense-Mediated Decay

Show evidence (5 references)

PMID:9425907 SUPPORT Human Clinical

"Here we demonstrate that SALL1 mutations cause TBS in a family with vertical transmission of TBS and in an unrelated family with a sporadic case of TBS. Both mutations are predicted to result in a prematurely terminated SALL1 protein lacking all putative DNA binding domains."

Original gene discovery, establishing truncating SALL1 variants as the cause of TBS.

PMID:17221874 SUPPORT Human Clinical

"We show that 46 out of the now 56 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..."

Defines the exon 2 truncating-variant hotspot.

CGGV:assertion_5883adb4-8c1e-46f0-8b23-1dd060763166-2026-03-20T040000.000Z SUPPORT Other

ClinGen Syndromic Disorders GCEP classifies the SALL1-TBS1 relationship as Definitive for autosomal dominant inheritance.

+ 2 more references

Truncated SALL1 Protein Escaping Nonsense-Mediated Decay

Despite carrying premature termination codons, the hotspot TBS alleles are transcribed and translated: mutant mRNA resists nonsense-mediated decay in patient fibroblasts, and truncated SALL1 protein is detectable in patient-derived cells, where it localizes to the cytoplasm. An allele that was NMD-susceptible was associated with a much milder phenotype, which is the human genetic basis for treating the stable truncated product, rather than reduced dosage, as the principal pathogenic species.

Truncated SALL1 causes TBS malformations partly through primary cilium dysfunction

SALL1 hgnc:10524

Downstream

Dominant-Negative Interference with SALL-Family Repressors

Aberrant Primary Cilium Formation Cytoplasmic truncated SALL1 binds the ciliogenesis suppressors CCP110 and CEP97, a function independent of transcriptional repression.

Show evidence (2 references)

PMID:18000979 SUPPORT In Vitro

"In SALL1, a mutant allele causing Townes-Brocks syndrome was unexpectedly resistant to NMD, whereas a different mutation causing a much milder phenotype was susceptible to NMD."

Allele-specific quantification in patient fibroblasts shows the TBS allele escapes NMD and correlates NMD susceptibility with milder disease.

PMID:18470945 SUPPORT In Vitro

"We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient."

Detects the truncated protein in patient-derived cells.

Dominant-Negative Interference with SALL-Family Repressors

Mechanism confidence: Provisional

Wild-type SALL1 is a zinc-finger transcriptional repressor that localizes to pericentromeric heterochromatin and recruits the NuRD corepressor complex through a conserved N-terminal motif. The truncated protein retains the SALL-interaction and repression regions but not the DNA-binding zinc fingers; it interacts with all SALL family members and is proposed to sequester them, reducing SALL-dependent repression of developmental target genes. The strongest support is the Sall1 allelic series in mouse: a truncating allele reproduces TBS features in heterozygotes whereas a null allele does not. Confidence is PROVISIONAL because the dominant-negative model does not account for the TBS phenotype of patients with whole-gene SALL1 deletions (see SALL1 Haploinsufficiency).

SALL1 hgnc:10524

SALL-dependent transcriptional repression GO:0000122 ↓ DECREASED

NuRD complex GO:0016581

Animal models

Sall1 truncating-allele mouse (Sall1-DeltaZn2-10) Mouse recapitulates Heterozygotes reproduce hearing loss, renal cystic hypoplasia and wrist bone anomalies, which the null allele does not.

Downstream

Ectopic Derepression of SALL Target Genes

Impaired Metanephric Kidney Development

Sensorineural Hearing Impairment The cochlear developmental step affected is not characterized; the edge rests on the heterozygous truncating-allele mouse phenotype.

Anal Atresia Anal malformation is seen only in mice homozygous for the truncating allele, not in heterozygotes, so the mouse supports that the truncated protein can perturb anorectal development but not the dosage at which this happens in heterozygous humans.

Show evidence (5 references)

PMID:12915476 SUPPORT Model Organism

"To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS."

A mouse allele expressing a truncated Sall1 reproduces TBS, where the null allele does not.

PMID:12915476 SUPPORT Model Organism

"We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins."

Provides the sequestration mechanism underlying the dominant-negative model.

PMID:18470945 SUPPORT Model Organism

"In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients."

Transgenic expression of the truncated protein on a wild-type background is sufficient for TBS-like limb malformation, a gain-of-product result.

+ 2 more references

Ectopic Derepression of SALL Target Genes

Mechanism confidence: Provisional

In mouse, the truncated protein's dominant-negative activity leads to ectopic activation of Sall-repressed targets, shown for Nppa in the developing heart and Shox2 in the developing limb. Which derepressed genes are responsible for which human malformations is not established; the cardiac Nppa finding has not been linked to the human congenital heart defects.

NPPA hgnc:7939 SHOX2 hgnc:10854

Downstream

Disrupted Autopod Digit Patterning

Show evidence (1 reference)

PMID:18470945 SUPPORT Model Organism

"TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb."

Direct demonstration of target-gene derepression by the truncated protein in mouse embryos.

SALL1 Whole- or Partial-Gene Deletion

A heterozygous copy-number loss removing all or part of SALL1 (reported sizes from a 3.4 kb intragenic deletion to multi-megabase deletions that also remove neighbouring genes). Deletions are a minority of SALL1-TBS and are missed by sequence analysis alone, so their detection requires quantitative PCR, MLPA or chromosomal microarray.

SALL1 hgnc:10524

Genetic context SALL1 hgnc:10524 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous deletion producing no truncated product; the allele acts by reduced SALL1 dosage.

Downstream

SALL1 Haploinsufficiency

Show evidence (2 references)

PMID:16429401 SUPPORT Human Clinical

"We applied quantitative real time PCR to detect and map SALL1 deletions in 240 patients with the clinical diagnosis of TBS, who were negative for SALL1 mutations. Deletions were found in three families."

Identifies SALL1 deletions in three of 240 sequence-negative clinically diagnosed families.

PMID:36833185 SUPPORT Human Clinical

"We report on a family with autosomal dominant hearing impairment and mild anal and skeletal anomalies, in whom a novel 350 kb SALL1 deletion, spanning exon 1 and the upstream region, was identified by array comparative genomic hybridization."

A further SALL1 deletion family detected by chromosomal microarray.

SALL1 Haploinsufficiency

Mechanism confidence: Provisional

Loss of one SALL1 allele without a truncated product. Human deletion carriers have TBS, which establishes that dosage reduction alone is pathogenic in humans even though heterozygous Sall1-null mice have no TBS phenotype. The phenotype of deletion carriers has been reported as milder than that of truncating-variant carriers, with fewer complete triads and no reported congenital heart disease, but a possibly higher rate of developmental delay; a later review of all reported deletions and truncating variants did not support the milder-phenotype correlation. The genotype-phenotype question remains open on a small number of deletion families.

SALL1 hgnc:10524

Animal models

Sall1 null mouse Mouse fails to recapitulate Heterozygous Sall1-null mice lack a TBS-like phenotype, whereas humans with SALL1 deletions have TBS.

Downstream

Sensorineural Hearing Impairment

Anal Stenosis

Show evidence (3 references)

PMID:16429401 SUPPORT Human Clinical

"These results confirm that SALL1 haploinsufficiency is sufficient to cause a mild TBS phenotype but suggest that it is not sufficient to cause the severe, classical form."

Deletion carriers establish haploinsufficiency as pathogenic and are reported as milder than point-mutation carriers.

PMID:36833185 SUPPORT Human Clinical

"We review the clinical findings of known individuals with SALL1 deletions and point out that the overall phenotype is milder, especially when compared with individuals who carry the recurrent p.Arg276Ter mutation, but with a possible higher risk of developmental delay."

Literature comparison of deletion carriers against p.Arg276Ter carriers.

PMID:22308078 REFUTE Human Clinical

"Taken together, they do not support the correlation of SALL1 deletions with a milder TBS phenotype and highlight a need for more robust clinical phenotyping combined with investigation of mutational mechanism."

Contradicts the claim that deletions produce a milder phenotype; it does not contradict haploinsufficiency being pathogenic.

Aberrant Primary Cilium Formation

Mechanism confidence: Hypothetical

Truncated SALL1 binds the ciliogenesis suppressors CCP110 and CEP97 and promotes the proteasomal degradation of LUZP1, reducing these negative regulators at the mother centriole. TBS patient fibroblasts, a CRISPR model cell line and TBS-modelled mouse embryonic fibroblasts form primary cilia more frequently, with altered cilium length and disassembly and aberrant Sonic hedgehog signal transduction. This places TBS in phenotypic overlap with the ciliopathies, but the evidence is cellular and the contribution of ciliary dysfunction to the malformations in vivo is untested.

Truncated SALL1 causes TBS malformations partly through primary cilium dysfunction

fibroblast CL:0000057

cilium assembly GO:0060271 ↑ INCREASED Sonic hedgehog signal transduction GO:0007224 ↕ DYSREGULATED

Downstream

Disrupted Autopod Digit Patterning Proposed rather than demonstrated: altered ciliary Hedgehog transduction would perturb limb patterning, which depends on Sonic hedgehog signalling.

Show evidence (3 references)

PMID:29395072 SUPPORT In Vitro

"This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls."

Increased ciliogenesis in patient and model cells.

PMID:29395072 SUPPORT In Vitro

"Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction."

Altered cilium dynamics and Hedgehog transduction in TBS-like cells.

PMID:32553112 SUPPORT In Vitro

"Truncated SALL1 increases the ubiquitin proteasome-mediated degradation of LUZP1."

A second ciliary regulator depleted by the truncated protein.

Impaired Metanephric Kidney Development

Sall1 is expressed in the metanephric mesenchyme surrounding the ureteric bud and is required for ureteric bud invasion, the first inductive step of metanephric development; complete loss gives renal agenesis. In heterozygous truncating-allele mice kidney development is partial, giving cystic hypoplasia. The human counterpart is congenital renal hypoplasia/dysplasia, which is the usual substrate of the chronic kidney disease in TBS.

metanephric mesenchyme stem cell CL:0000324

metanephros development GO:0001656 ⚠ ABNORMAL ureteric bud development GO:0001657 ⚠ ABNORMAL

Animal models

Sall1 null mouse Mouse recapitulates Homozygous loss identifies ureteric bud invasion as the Sall1-dependent step of metanephric development.

Downstream

Renal Hypoplasia

Polycystic Kidney Dysplasia

Show evidence (2 references)

PMID:11688560 SUPPORT Model Organism

"Sall1 is expressed in the metanephric mesenchyme surrounding ureteric bud; homozygous deletion of Sall1 results in an incomplete ureteric bud outgrowth, a failure of tubule formation in the mesenchyme and an apoptosis of the mesenchyme."

Defines the developmental step that requires Sall1.

PMID:11688560 SUPPORT Model Organism

"Sall1 is therefore essential for ureteric bud invasion, the initial key step for metanephros development."

States the conclusion that Sall1 gates metanephric induction.

Disrupted Autopod Digit Patterning

Abnormal specification of digit number and identity in the anterior (preaxial) autopod, producing thumb duplication and triphalangeal thumbs, with homologous foot anomalies (overlapping toes, flat feet). The radius is characteristically spared, which separates TBS from the radial-ray syndromes. The disorder-specific patterning input is the truncated SALL1 protein; which patterning signal it perturbs is not settled, with target-gene derepression (Shox2) and ciliary Hedgehog transduction both proposed.

anterior/posterior pattern specification GO:0009952 ⚠ ABNORMAL embryonic limb morphogenesis GO:0030326 ⚠ ABNORMAL

Downstream

Preaxial Hand Polydactyly

Triphalangeal Thumb

Thumb Hypoplasia

Overlapping Toes

Show evidence (2 references)

PMID:18470945 SUPPORT Model Organism

"In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients."

Truncated SALL1 is sufficient to produce TBS-like limb malformation.

PMID:20301618 SUPPORT Human Clinical

"triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius"

GeneReviews describes the preaxial digit pattern and the sparing of the radius.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

37

Cardiovascular 2

Congenital Heart Defect OCCASIONAL Abnormal heart morphology HP:0001627

Onset: CONGENITAL

Show evidence (5 references)

PMID:20301618 SUPPORT Human Clinical

"Congenital heart disease occurs in 15% of affected individuals."

15% supports OCCASIONAL (5-29%).

PMID:40348827 SUPPORT Human Clinical

"Nearly 19% (37/196) of individuals had congenital heart defect."

19% in the literature review, also within OCCASIONAL.

PMID:11484202 SUPPORT Human Clinical

"Unique cardiac anomalies seen in this family include lethal truncus arteriosus in one patient and a lethal complicated defect, including pulmonary valve atresia, in a second patient."

Severe conotruncal and valvular defects in a TBS family.

+ 2 more references

Tetralogy of Fallot HP:0001636

Onset: CONGENITAL

Show evidence (1 reference)

PMID:36833185 SUPPORT BACKGROUND Human Clinical

"congenital heart defects (tetralogy of Fallot and ventricular septal defects)"

Introductory summary of reported TBS heart defects in a case report, not the paper's own finding.

Digestive 4

Anal Atresia HP:0002023

Onset: CONGENITAL

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears"

GeneReviews lists imperforate anus in the defining triad.

PMID:40348827 SUPPORT Human Clinical

"The clinical triad was identified in 95/191 (49.7%) of patients with dysplastic ears being the most common sign (83.5%), followed by thumb malformations (74.2%) and anorectal malformation (66.7%)."

Anorectal malformation of any type in 66.7% of 207 reported patients.

Anal Stenosis HP:0002025

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears"

GeneReviews includes anal stenosis in the triad.

Anteriorly Placed Anus HP:0001545

Onset: CONGENITAL

Show evidence (2 references)

PMID:36833185 SUPPORT Human Clinical

"She presented with a ventrally positioned anus, pantonal sensorineural hearing loss (prevalent in the left ear) of mild-medium severity, and speech delay."

Ventrally positioned anus in a SALL1-deletion proband.

ORPHA:857 SUPPORT Other

"HP:0001545 | Anteriorly placed anus | Frequent (79-30%)"

Orphanet annotation for Townes-Brocks syndrome (parent concept); no frequency is asserted here because the Orphanet record is not SALL1-specific.

Constipation HP:0002019

Show evidence (2 references)

ORPHA:857 SUPPORT Other

"HP:0002019 | Constipation | Frequent (79-30%)"

Orphanet annotation for Townes-Brocks syndrome (parent concept); no frequency is asserted here because the record is not SALL1-specific.

PMID:20301618 SUPPORT Human Clinical

"Surveillance: Assess for constipation and assess growth and thyroid function at each visit"

GeneReviews surveillance for constipation.

Ear 6

Dysplastic Ears VERY_FREQUENT Abnormal pinna morphology HP:0000377

Onset: CONGENITAL

Show evidence (2 references)

PMID:40348827 SUPPORT Human Clinical

"The clinical triad was identified in 95/191 (49.7%) of patients with dysplastic ears being the most common sign (83.5%), followed by thumb malformations (74.2%) and anorectal malformation (66.7%)."

Dysplastic ears in 83.5% of reported patients supports VERY_FREQUENT (80-100%).

PMID:20301618 SUPPORT Human Clinical

"dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment)"

GeneReviews description of the ear anomaly.

Overfolded Helix HP:0000396

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment)"

GeneReviews names overfolded superior helices.

Microtia HP:0008551

Onset: CONGENITAL

Show evidence (1 reference)

PMID:36833185 SUPPORT BACKGROUND Human Clinical

"Among ear anomalies, the most typical are overfolded superior helices, preauricular tags and microtia, frequently associated with hearing impairment (sensorineural and/or conductive)."

Introductory summary of the TBS ear phenotype in a case report; the observation is not this paper's own result.

Hearing Impairment FREQUENT HP:0000365

Show evidence (2 references)

PMID:40348827 SUPPORT Human Clinical

"Additionally, 128/197 (65.0%) of patients were diagnosed with deafness, which was often sensorineural and mild to moderate."

65% in the literature review supports FREQUENT (30-79%).

PMID:40348827 SUPPORT Human Clinical

"Renal failure and deafness can occur at any age, making follow-up essential."

Hearing loss can appear at any age, supporting lifelong surveillance.

Sensorineural Hearing Impairment HP:0000407

Show evidence (2 references)

PMID:40348827 SUPPORT Human Clinical

"In most cases, deafness was post lingual, sensorineural, bilateral, mild to moderate."

Characterizes the hearing loss in a 49-patient series.

PMID:38296632 SUPPORT Human Clinical

"while over 60% (65/108) exhibited sensorineural HL (SNHL)."

Sensorineural loss predominates in 108 patients with hearing data.

Conductive Hearing Impairment HP:0000405

Show evidence (2 references)

PMID:38296632 SUPPORT Human Clinical

"Among the 108 patients, 11.1% (12/108) were diagnosed with conductive HL (CHL) or mixed HL"

11.1% conductive or mixed; the source does not separate the two, so no frequency band is asserted for conductive loss alone.

PMID:38296632 SUPPORT Human Clinical

"Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient."

Structural middle and inner ear malformation on imaging.

Endocrine 2

Hypothyroidism HP:0000821

Show evidence (2 references)

PMID:40348827 SUPPORT Human Clinical

"Endocrinological features were present in 28/196 (14.3%) of patients with 5.6% having hypothyroidism and 4% having growth retardation."

Hypothyroidism in 5.6% of reported patients.

PMID:38296632 SUPPORT Human Clinical

"By comprehensive clinical evaluations, we further provide evidence for the causal relationship between SALL1 variation and certain endocrine abnormalities."

Family segregation data supporting endocrine involvement.

Growth Hormone Deficiency Decreased response to growth hormone stimulation test HP:0000824

Show evidence (1 reference)

PMID:23894113 SUPPORT Human Clinical

"Patient 1 appears to be the first known case of growth hormone deficiency, and Patient 2 extends the number of documented mutation cases with hypothyroidism to four."

Growth hormone deficiency in a molecularly confirmed patient.

Eye 4

Duane Anomaly HP:0009921

Onset: CONGENITAL

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."

GeneReviews lists Duane anomaly as rare.

PMID:31981611 SUPPORT Human Clinical

"Ophthalmic findings have been rarely reported and include congenital cataract, microphthalmia, optic nerve atrophy, coloboma, epibulbar dermoid, and dysinnervation patterns, such as Duane syndrome and gustatory lacrimation."

Summarizes the reported ocular spectrum including Duane syndrome.

Iris Coloboma HP:0000612

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."

GeneReviews lists iris coloboma as rare.

Congenital Cataract Developmental cataract HP:0000519

Onset: CONGENITAL

Show evidence (1 reference)

PMID:17221874 SUPPORT Human Clinical

"We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia."

First report of congenital cataract in SALL1-TBS.

Microphthalmia HP:0000568

Onset: CONGENITAL

Show evidence (1 reference)

PMID:17221874 SUPPORT Human Clinical

"We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia."

Microphthalmia in SALL1-TBS.

Genitourinary 10

Renal Hypoplasia HP:0000089

Onset: CONGENITAL

Sequelae: Chronic Kidney Disease

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."

GeneReviews lists renal hypoplasia among the structural anomalies.

PMID:19204018 SUPPORT Human Clinical

"Renal involvement (hypo-dysplasia, multicystic kidneys or unilateral absence) is observed in almost half of patients and may progress to end-stage renal failure in childhood."

Renal hypodysplasia as the principal renal lesion.

Polycystic Kidney Dysplasia HP:0000113

Onset: CONGENITAL

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."

GeneReviews lists polycystic kidneys.

PMID:19204018 SUPPORT Human Clinical

"Renal involvement (hypo-dysplasia, multicystic kidneys or unilateral absence) is observed in almost half of patients and may progress to end-stage renal failure in childhood."

Multicystic kidneys among TBS renal lesions.

Horseshoe Kidney HP:0000085

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."

GeneReviews lists horseshoe kidney.

Ectopic Kidney HP:0000086

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."

GeneReviews lists ectopia.

Vesicoureteral Reflux HP:0000076

Sequelae: Chronic Kidney Disease

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."

GeneReviews lists vesicoureteral reflux.

Chronic Kidney Disease HP:0012622

Course: PROGRESSIVE

Sequelae: Kidney Failure

Show evidence (4 references)

PMID:38296632 SUPPORT Human Clinical

"TBS-related renal impairment could present as ESRD during early childhood or progress insidiously from asymptomatic mild reduced clearance"

Supports the PROGRESSIVE clinical course: renal impairment can progress insidiously from mildly reduced clearance.

PMID:40348827 SUPPORT Human Clinical

"Kidney structural malformations and chronic renal failure affected 81/191 (42.4%) and 56/191 (29.3%) of patients (9.5% of which progressed to end-stage renal failure), respectively."

Chronic renal failure in 29.3% of reported patients.

PMID:40348827 SUPPORT Human Clinical

"Notably, 3 patients had chronic renal failure without abnormalities on kidney ultrasound."

CKD can occur without detectable structural anomaly.

+ 1 more reference

Kidney Failure Stage 5 chronic kidney disease HP:0003774

Show evidence (4 references)

PMID:38296632 SUPPORT Human Clinical

"Eleven individuals were reported to get diagnosed between neonatal birth and middle childhood (0-11 years old), 3 of them had already advanced to end-stage renal disease (ESRD), necessitating dialysis or renal transplantation."

Kidney failure already present in childhood in 3 of 11 patients.

PMID:19204018 SUPPORT Human Clinical

"Renal involvement (hypo-dysplasia, multicystic kidneys or unilateral absence) is observed in almost half of patients and may progress to end-stage renal failure in childhood."

ESKD can be reached in childhood.

PMID:33438842 SUPPORT Human Clinical

"Among 44 adult cases of TBS with genetic confirmation (including our two cases), 10 had kidney disease."

Kidney disease in 10 of 44 molecularly confirmed adults, from a literature review of adult-diagnosed TBS.

+ 1 more reference

Focal Segmental Glomerulosclerosis HP:0000097

Show evidence (1 reference)

PMID:19204018 SUPPORT Human Clinical

"Both exhibited severe chronic renal failure and kidney hypodysplasia by imaging studies while focal and segmental glomerulosclerosis (FSGS) was demonstrated in one case."

FSGS on biopsy in an adult TBS patient.

Cryptorchidism HP:0000028

Onset: CONGENITAL

Show evidence (2 references)

PMID:16088922 SUPPORT Human Clinical

"Rare phenotypical features among mutation positive patients include hypothyroidism, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, dorsal hypoplasia of the corpus callosum, and umbilical hernia."

Cryptorchidism in SALL1 mutation-positive patients.

PMID:40348827 SUPPORT Human Clinical

"A genital anomaly was observed in 24/96 (25%) of males and in only 3/93 (3.23%) of females."

Genital anomalies of any type in 25% of males; the review does not give the cryptorchidism share, so no frequency is asserted.

Hypospadias HP:0000047

Onset: CONGENITAL

Show evidence (1 reference)

PMID:36833185 SUPPORT Human Clinical

"71 kb SALL1 deletion was reported in a patient with bilateral sensorineural hearing impairment, anal stenosis, broad fingertips, mild global developmental delay, and penile hypospadias."

Penile hypospadias in a SALL1-deletion carrier.

Head and Neck 1

Preauricular Skin Tag HP:0000384

Onset: CONGENITAL

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment)"

GeneReviews names preauricular tags.

Limbs 5

Preaxial Hand Polydactyly HP:0001177

Onset: CONGENITAL

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"thumb malformations (duplication of the thumb"

GeneReviews lists thumb duplication among the thumb malformations.

PMID:40348827 SUPPORT Human Clinical

"thumb malformations were present in 53.1% with mostly triphalangeal and/or duplicated thumbs"

In the authors' 49-patient series, thumb malformations were mostly triphalangeal and/or duplicated thumbs.

Triphalangeal Thumb HP:0001199

Onset: CONGENITAL

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius"

GeneReviews lists triphalangeal thumbs.

PMID:40348827 SUPPORT Human Clinical

"thumb malformations were present in 53.1% with mostly triphalangeal and/or duplicated thumbs"

Triphalangeal thumb is one of the two dominant thumb anomalies.

Thumb Hypoplasia VERY_RARE Aplasia/Hypoplasia of the thumb HP:0009601

Onset: CONGENITAL

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius"

GeneReviews describes thumb hypoplasia as rare, supporting VERY_RARE.

PMID:11484202 SUPPORT Human Clinical

"In addition, hypoplastic thumbs were seen in two individuals in this family and should, therefore, be considered a true feature of TBS."

Family report establishing thumb hypoplasia as part of TBS.

Overlapping Toes HP:0001845

Onset: CONGENITAL

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"Foot malformations (flat feet, overlapping toes) and genitourinary malformations are common."

GeneReviews lists overlapping toes among common foot malformations.

PMID:40348827 SUPPORT Human Clinical

"Lower limb malformations were mainly clinodactyly and overlapping toe"

Overlapping toe is one of the two main lower-limb anomalies in the series.

Pes Planus HP:0001763

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Foot malformations (flat feet, overlapping toes) and genitourinary malformations are common."

GeneReviews lists flat feet among common foot malformations.

Nervous System 2

Developmental Delay OCCASIONAL Global developmental delay HP:0001263

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"Developmental delay and/or learning difficulties occur in approximately 15% of affected individuals."

15% supports OCCASIONAL (5-29%).

PMID:40348827 SUPPORT Human Clinical

"We undertook a review of patients with DD and/or ID and found a proportion of 8% (14/175) having DD/ID"

8% in the literature review, within OCCASIONAL.

Chiari Type I Malformation HP:0007099

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."

GeneReviews lists Chiari I malformation as rare.

Growth 1

Growth Delay HP:0001510

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."

GeneReviews lists growth deficiency as rare.

🧬

Genetic Associations

1

SALL1

Gene: SALL1 hgnc:10524 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

CGGV:assertion_5883adb4-8c1e-46f0-8b23-1dd060763166-2026-03-20T040000.000Z SUPPORT Other

ClinGen Definitive gene-disease validity.

PMID:9973281 SUPPORT Human Clinical

"All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains."

Early mutation series establishing the truncating pattern.

PMID:40348827 SUPPORT Human Clinical

"A significant increase in deafness, dysplastic ear, and thumb malformations and a significant decrease in renal failure were observed in the individuals carrying a variant located downstream of the region, but the patients were significantly younger."

Genotype-phenotype association by variant position, with the age confounder the authors note.

💊

Medical Actions

9

Surgical Repair of Anorectal Malformation

Action: anorectal malformation repair Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Immediate neonatal surgical management of imperforate anus, followed by bowel management for constipation (stool softeners, prokinetics, osmotic agents or laxatives).

Target Phenotypes: Imperforate anus HP:0002023

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"Immediate surgical intervention for imperforate anus; stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation"

GeneReviews treatment of manifestations.

Surgery for Severe Hand Malformations

Action: hand surgery Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical correction of severe thumb malformations.

Target Phenotypes: Preaxial hand polydactyly HP:0001177 Triphalangeal thumb HP:0001199

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"surgery for severe malformations of the hands"

GeneReviews treatment of manifestations.

Hearing Surveillance and Early Treatment of Hearing Loss

Action: annual audiology evaluation Ontology label: Audiometric Test NCIT:C38036

Platform: Other

Annual audiology evaluation, with early treatment of hearing loss when identified. Because hearing loss can be postlingual and appear at any age, surveillance continues after a normal newborn screen. Medications with otic toxicity should be avoided.

Target Phenotypes: Hearing impairment HP:0000365

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"annual audiology evaluation; monitor kidney function annually in individuals with and without kidney anomalies, even if kidney function is normal on initial examination"

GeneReviews surveillance recommendation for hearing and kidneys.

PMID:20301618 SUPPORT Human Clinical

"Agents/circumstances to avoid: Medications that cause renal or otic toxicity."

GeneReviews agents to avoid.

Lifelong Kidney Function Surveillance

Action: annual kidney function testing Ontology label: Renal Function Test NCIT:C74972

Platform: Other

Annual monitoring of kidney function in every affected individual, including those with structurally normal kidneys and normal function at first evaluation, because CKD can develop at any age. Nephrotoxic medications should be avoided. At-risk relatives should have their genetic status clarified so that kidney disease can be detected early.

Target Phenotypes: Chronic kidney disease HP:0012622

Show evidence (3 references)

PMID:20301618 SUPPORT Human Clinical

"annual audiology evaluation; monitor kidney function annually in individuals with and without kidney anomalies, even if kidney function is normal on initial examination"

GeneReviews annual kidney function surveillance.

PMID:19204018 SUPPORT Human Clinical

"Regular assessment of glomerular filtration rate is mandatory throughout life in all TBS patients."

Recommendation from adult-onset kidney failure cases.

PMID:20301618 SUPPORT Human Clinical

"Clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with SALL1-TBS in order to identify as early as possible those who would benefit from clinical evaluation and prompt initiation of treatment for kidney disease and other features of SALL1-TBS."

GeneReviews cascade evaluation of relatives.

Hemodialysis

Action: hemodialysis Ontology label: Hemodialysis NCIT:C15248

Platform: Other

Hemodialysis for end-stage kidney disease.

Target Phenotypes: End-stage kidney disease HP:0003774

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"hemodialysis and possibly kidney transplantation for ESKD"

GeneReviews treatment for ESKD.

Kidney Transplantation

Action: kidney transplantation Ontology label: Kidney Transplantation NCIT:C15265

Platform: Surgery

Kidney transplantation for end-stage kidney disease.

Target Phenotypes: End-stage kidney disease HP:0003774

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"hemodialysis and possibly kidney transplantation for ESKD"

GeneReviews treatment for ESKD.

Growth Hormone Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: somatropin CHEBI:749556

Platform: Protein replacement

Growth hormone for those with documented growth hormone deficiency; growth and thyroid function are assessed at each visit.

Target Phenotypes: Growth hormone deficiency HP:0000824

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"growth hormone therapy for those with growth hormone deficiency"

GeneReviews treatment of manifestations.

Cardiac Management of Congenital Heart Defects

Action: surgical or medical cardiac treatment Ontology label: Therapeutic Procedure NCIT:C49236

Surgical or medical treatment of congenital heart defects under a cardiologist, following cardiac evaluation at diagnosis.

Target Phenotypes: Congenital heart defect HP:0001627

Show evidence (1 reference)

PMID:20301618 SUPPORT Human Clinical

"surgery or medical treatment by cardiologist for congenital heart defects"

GeneReviews treatment of manifestations for congenital heart defects.

Genetic Counseling

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal dominant counseling with a 50% recurrence risk to offspring of an affected person; evaluation of at-risk relatives; prenatal and preimplantation testing once the familial variant is known, and prenatal cardiac and nephrology evaluation in affected pregnant women.

Show evidence (2 references)

PMID:20301618 SUPPORT Human Clinical

"Once the SALL1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews genetic counseling.

PMID:20301618 SUPPORT Human Clinical

"Pregnancy management: Consider prenatal cardiac and nephrology evaluations in pregnant women with SALL1-TBS."

GeneReviews pregnancy management.

🔬

Diagnosis

1

Clinical and molecular diagnosis of SALL1-TBS

Suspected in a child with an anorectal malformation, dysplastic ears or hearing loss, and preaxial thumb anomalies with a normal radius, and increasingly in children and adults ascertained through hearing-loss or kidney-disease gene panels with incomplete or atypical features. Confirmed by a heterozygous pathogenic SALL1 variant. Because deletions are missed by sequencing, a sequencing-negative patient with a suggestive phenotype should have copy-number analysis.

Kidney-gene-panel cohorts identify SALL1 variants in patients whose presentation is non-syndromic CAKUT or a branchio-oto-renal-like combination of ear anomalies, hearing loss and CAKUT, sometimes first diagnosed in adolescence or adulthood.

Show evidence (3 references)

PMID:20301618 SUPPORT Human Clinical

"The diagnosis of SALL1-TBS is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in SALL1 identified by molecular genetic testing."

GeneReviews diagnostic criterion.

PMID:36833185 SUPPORT Human Clinical

"Chromosomal microarray analysis is still a valuable tool in the identification of atypical/mild TBS cases, which are likely underestimated."

Supports copy-number testing for deletions.

PMID:40658219 SUPPORT Human Clinical

"Some cases present with atypical features overlapping with TBS BOR-like syndrome or isolated CAKUT, rather than with typical TBS1."

Atypical presentations ascertained through a CKD cohort.

📊

Prevalence

2

Spain, ECEMC consecutive series of live births, 1976-1997

Birth Prevalence 0.42 per 100,000 live births 1–9 per 1,000,000 (births)

Minimal estimate of 0.42 per 100,000 live births (6 cases among 1,431,368 surveyed live births). This is a clinical, pre-molecular ascertainment of Townes-Brocks syndrome and so covers the parent concept (SALL1 and the rarer DACT1 form) rather than SALL1-confirmed disease; the authors present it as a minimum.

Show evidence (1 reference)

PMID:10083645 SUPPORT Human Clinical

"The minimal estimated frequency of Townes-Brocks syndrome in our data is 0.42 cases per 100,000 liveborn infants."

Population-based birth prevalence from a Spanish malformation registry.

Europe

Point Prevalence 1–9 per 1,000,000

Orphanet class 1-9 / 1,000,000 for Europe. The Orphanet record (ORPHA:857) is for Townes-Brocks syndrome as a whole, not SALL1-TBS specifically. A large hearing-loss cohort study argues the true prevalence is underestimated because mild and atypical presentations go unrecognized.

Show evidence (2 references)

ORPHA:857 SUPPORT Other

"1-9 / 1 000 000 | Europe | Point prevalence | ORPHANET"

Orphanet epidemiology table for Townes-Brocks syndrome.

PMID:38296632 SUPPORT Human Clinical

"We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS."

Screening of 20,666 hearing-loss probands identified TBS families not previously diagnosed, supporting under-ascertainment.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Townes-Brocks Syndrome 1:

Townes-Brocks Syndrome 2 Not Yet Curated MONDO:0054582

Overlapping Features DACT1-related autosomal dominant syndrome with imperforate anus, renal, genitourinary and ear anomalies overlapping TBS.

Distinguishing Features

Heterozygous DACT1 rather than SALL1 variant.
Thumb malformations were not part of the phenotype in the first reported DACT1 family.

Show evidence (1 reference)

PMID:28054444 SUPPORT Human Clinical

"A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies."

The DACT1 family phenotype, which lists no thumb anomaly.

Craniofacial Microsomia MONDO:0015397

Overlapping Features Ear anomalies and preauricular tags can make SALL1 disease resemble Goldenhar syndrome.

Distinguishing Features

Anorectal malformation and triphalangeal or duplicated thumbs point to SALL1.

Show evidence (1 reference)

PMID:9973281 SUPPORT Human Clinical

"We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome."

SALL1 disease can mimic Goldenhar syndrome.

VACTERL Association Not Yet Curated MONDO:0008642

Overlapping Features Anorectal, renal, limb and cardiac anomalies overlap VACTERL, and TBS is thought to be under-recognized among patients labelled as VACTERL.

Distinguishing Features

Dysplastic ears and sensorineural hearing loss point to SALL1.
Radial hypoplasia and vertebral and tracheoesophageal anomalies favor VACTERL.

Show evidence (1 reference)

PMID:23894113 SUPPORT BACKGROUND Human Clinical

"but is probably much higher due to common shared characteristics with VATER association and subtle variable phenotypes in many TBS patients"

Introductory statement on overlap with VATER association.

Fanconi Anemia MONDO:0019391

Overlapping Features Fanconi anemia can present with thumb anomalies and a TBS-like malformation pattern; a chromosome breakage test or FA gene testing separates them.

Distinguishing Features

Radial hypoplasia, skin pigmentary changes, bone marrow failure and chromosome fragility favor Fanconi anemia.
TBS thumb anomalies occur without radial hypoplasia.

Show evidence (1 reference)

PMID:19622403 SUPPORT Other

"FA patients may also present with a phenotype characteristic of Seckel syndrome, Nijmegen breakage syndrome, Dubowitz syndrome, Holt-Oram syndrome, thrombocytopenia absent radius (TAR) syndrome, Townes-Brocks syndrome"

A Fanconi anemia review naming TBS among FA phenocopies.

🐁

Animal Models

2

Sall1 truncating-allele mouse (Sall1-DeltaZn2-10)

Knock-in allele expressing a truncated Sall1 that lacks zinc fingers 2-10, designed to mimic human TBS truncating alleles. Also used, as Sall1TBS, to study adult kidney injury.

Species

Mouse

Genotype

Sall1 DeltaZn2-10 (heterozygous and homozygous)

Publication

PMID:12915476

Pathograph links

Dominant-Negative Interference with SALL-Family Repressors recapitulates fidelity: moderate Heterozygotes reproduce hearing loss, renal cystic hypoplasia and wrist bone anomalies, which the null allele does not.

Limitations: Heterozygotes do not show the anorectal or thumb anomalies that define human TBS; anal deformity appears only in homozygotes. The allele is a mouse-designed truncation rather than a human hotspot variant.

Readouts

TBS-like phenotype in heterozygotes

Direction: ALTERED

Interpretation: Presence of hearing, renal and wrist phenotypes with one truncating allele.

Show evidence (1 reference)

PMID:12915476 SUPPORT Model Organism

"Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities."

Reports the heterozygous phenotype.

Show evidence (1 reference)

PMID:12915476 SUPPORT Model Organism

"To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS."

The model was built to test the dominant-negative hypothesis.

Sall1 null mouse

Targeted Sall1 deletion. Homozygotes die perinatally with kidney agenesis or severe dysgenesis; heterozygotes have no TBS-like phenotype.

Species

Mouse

Genotype

Sall1 null (heterozygous and homozygous)

Publication

PMID:11688560

Pathograph links

Impaired Metanephric Kidney Development recapitulates fidelity: moderate Homozygous loss identifies ureteric bud invasion as the Sall1-dependent step of metanephric development.

Limitations: Homozygous agenesis is far more severe than the human heterozygous hypodysplasia spectrum.

Show evidence (1 reference)

PMID:11688560 SUPPORT Model Organism

"We have isolated a mouse homolog of SALL1 (Sall1) and found that mice deficient in Sall1 die in the perinatal period and that kidney agenesis or severe dysgenesis are present."

Homozygous null kidney phenotype.

SALL1 Haploinsufficiency fails to recapitulate fidelity: low Heterozygous Sall1-null mice lack a TBS-like phenotype, whereas humans with SALL1 deletions have TBS.

Limitations: Species difference in SALL1 dosage sensitivity; the mouse cannot be used to model the human deletion phenotype.

Show evidence (2 references)

PMID:16429401 SUPPORT BACKGROUND Model Organism

"This assumption was strongly contradicted by a Sall1 mouse knock-out, because neither hetero- nor homozygous knock-out mutants displayed a TBS-like phenotype."

The heterozygous knockout has no TBS-like phenotype; quoted from the background of a human deletion study.

+ 1 more reference

{ }

Source YAML

click to show

name: Townes-Brocks Syndrome 1
creation_date: "2026-09-23T00:00:00Z"
description: >-
  An autosomal dominant multiple congenital anomaly syndrome caused by
  heterozygous germline pathogenic variants in SALL1, which encodes a
  zinc-finger transcriptional repressor of the spalt family. The classic triad
  is an anorectal malformation (imperforate anus or anal stenosis), dysplastic
  external ears (overfolded superior helices, preauricular tags) with
  sensorineural and/or conductive hearing impairment, and thumb malformations
  (preaxial polydactyly, triphalangeal thumb, rarely thumb hypoplasia) without
  radial hypoplasia. Congenital anomalies of the kidney and urinary tract,
  chronic kidney disease that can reach kidney failure from the neonatal period
  onwards, foot and genital malformations, congenital heart disease, and less
  often developmental delay, endocrine deficiencies and ocular anomalies complete
  the picture. The malformations are present at birth and most patients are
  recognized in infancy or childhood, but expressivity is highly variable within
  families and mildly affected adults are often diagnosed only after an affected
  child, or after presenting with kidney failure. Most pathogenic variants are
  truncating alleles in a hotspot of exon 2 whose products escape
  nonsense-mediated decay and are thought to act dominant-negatively on the SALL
  protein family; whole- or partial-gene deletions (haploinsufficiency) are rarer
  and have been associated with a milder phenotype, although this correlation is
  disputed.
category: Genetic
synonyms:
- TBS1
- SALL1-related Townes-Brocks syndrome
- SALL1-TBS
- REAR syndrome
- renal-ear-anal-radial syndrome
- deafness, sensorineural, with imperforate anus and thumb anomalies
- anus, imperforate, with hand, foot, and ear anomalies
- Townes-Brocks branchiootorenal-like syndrome
parents:
- Multiple Congenital Anomaly Syndrome
- Syndromic Hearing Loss
- Congenital Anomaly of the Kidney and Urinary Tract
- Anorectal Malformation
disease_term:
  preferred_term: Townes-Brocks syndrome 1
  term:
    id: MONDO:0054581
    label: Townes-Brocks syndrome 1
references:
- reference: PMID:20301547
  title: "SALL4-Related Disorders."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301618
  title: SALL1-Related Townes-Brocks Syndrome.
  tags:
  - GeneReviews
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: KIDNEY_URINARY_TRACT
  - classification_value: DISORDER_OF_EAR
  isds_skeletal_category:
  - classification_value: polydactyly_syndactyly_triphalangism
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 40 "Polydactyly-Syndactyly-Triphalangism group". The
      schema's ISDSNosologyGroupEnum description for this group lists
      "Townes-Brocks syndrome (SALL1)" among its members. MONDO likewise places
      MONDO:0054581 under MONDO:0800066 polydactyly-syndactyly-triphalangism.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  de_novo_rate: About 50% of individuals diagnosed with SALL1-TBS
  description: >-
    Heterozygous SALL1 pathogenic variants are transmitted in an autosomal
    dominant manner with a 50% risk to each child of an affected individual.
    About half of probands carry a de novo variant, and de novo variants arise
    predominantly on the paternally derived chromosome 16 without an obvious
    paternal age effect. Expressivity is highly variable within and between
    families; mildly affected parents are often recognized only after a more
    severely affected child, which is one reason for testing apparently
    unaffected at-risk relatives. Penetrance is usually described as complete,
    but a Chinese hearing-loss cohort reported apparently incomplete penetrance
    in the transmitting generation of several families.
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SALL1-TBS is inherited in an autosomal dominant manner. About 50% of individuals diagnosed with SALL1-TBS have the disorder as the result of a de novo pathogenic variant."
    explanation: >-
      GeneReviews states the inheritance pattern and the de novo fraction.
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with SALL1-TBS has a 50% chance of inheriting the pathogenic variant."
    explanation: >-
      GeneReviews states the 50% transmission risk to each child of an
      affected individual.
  - reference: PMID:16892410
    reference_title: "SALL1 mutations in sporadic Townes-Brocks syndrome are of predominantly paternal origin without obvious paternal age effect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations were of paternal origin in 14 of 16 cases (87.5%). Paternal origin was independent of the mutation type."
    explanation: >-
      Parent-of-origin analysis in 16 sporadic families shows de novo SALL1
      variants arise mostly on the paternal allele.
  - reference: PMID:20520617
    reference_title: "Phenotypic variability in a family with Townes-Brocks syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is wide clinical variation in TBS; however, most affected parents are usually mildly affected and may have similarly or more severely affected children."
    explanation: >-
      Documents intrafamilial variable expressivity and the pattern of a mildly
      affected transmitting parent.
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring."
    explanation: >-
      Reports apparently reduced penetrance in the transmitting generation, a
      qualification of the usual statement that penetrance is complete.
prevalence:
- population: Spain, ECEMC consecutive series of live births, 1976-1997
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.42
  rate_denominator: LIVE_BIRTHS
  notes: >-
    Minimal estimate of 0.42 per 100,000 live births (6 cases among 1,431,368
    surveyed live births). This is a clinical, pre-molecular ascertainment of
    Townes-Brocks syndrome and so covers the parent concept (SALL1 and the rarer
    DACT1 form) rather than SALL1-confirmed disease; the authors present it as a
    minimum.
  evidence:
  - reference: PMID:10083645
    reference_title: "[The Townes-Brocks syndrome in Spain: the epidemiological aspects in a consecutive series of cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The minimal estimated frequency of Townes-Brocks syndrome in our data is 0.42 cases per 100,000 liveborn infants."
    explanation: >-
      Population-based birth prevalence from a Spanish malformation registry.
- population: Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  notes: >-
    Orphanet class 1-9 / 1,000,000 for Europe. The Orphanet record (ORPHA:857)
    is for Townes-Brocks syndrome as a whole, not SALL1-TBS specifically. A
    large hearing-loss cohort study argues the true prevalence is underestimated
    because mild and atypical presentations go unrecognized.
  evidence:
  - reference: ORPHA:857
    reference_title: "Townes-Brocks syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet epidemiology table for Townes-Brocks syndrome.
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS."
    explanation: >-
      Screening of 20,666 hearing-loss probands identified TBS families not
      previously diagnosed, supporting under-ascertainment.
pathophysiology:
- name: SALL1 Truncating Variant
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A heterozygous germline nonsense or frameshift SALL1 variant, clustering in
    an ~800 bp hotspot in exon 2 between the glutamine-rich domain and the first
    double zinc-finger domain. The predicted product is a truncated protein that
    retains the N-terminal repression and SALL-interaction regions but lacks the
    C-terminal DNA-binding double zinc fingers. The recurrent c.826C>T
    (p.Arg276Ter) accounts for roughly half of simplex cases and has been
    associated with a more complete phenotype, including congenital heart
    defects.
  genes:
  - preferred_term: SALL1
    term:
      id: hgnc:10524
      label: SALL1
  genetic_context:
    gene:
      preferred_term: SALL1
      term:
        id: hgnc:10524
        label: SALL1
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Truncating alleles that escape nonsense-mediated decay and are thought to
      act through the truncated product rather than by loss of one allele. The
      dominant-negative assignment rests on mouse genetics and patient-cell
      work (see downstream nodes); ClinGen records the mechanism as either
      haploinsufficiency or dominant-negative.
  evidence:
  - reference: PMID:9425907
    reference_title: "Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we demonstrate that SALL1 mutations cause TBS in a family with vertical transmission of TBS and in an unrelated family with a sporadic case of TBS. Both mutations are predicted to result in a prematurely terminated SALL1 protein lacking all putative DNA binding domains."
    explanation: >-
      Original gene discovery, establishing truncating SALL1 variants as the
      cause of TBS.
  - reference: PMID:17221874
    reference_title: "Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that 46 out of the now 56 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."
    explanation: >-
      Defines the exon 2 truncating-variant hotspot.
  - reference: CGGV:assertion_5883adb4-8c1e-46f0-8b23-1dd060763166-2026-03-20T040000.000Z
    reference_title: "SALL1 / Townes-Brocks syndrome 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SALL1 | HGNC:10524 | Townes-Brocks syndrome 1 | MONDO:0054581 | AD | Definitive"
    explanation: >-
      ClinGen Syndromic Disorders GCEP classifies the SALL1-TBS1 relationship
      as Definitive for autosomal dominant inheritance.
  - reference: CGGV:assertion_5883adb4-8c1e-46f0-8b23-1dd060763166-2026-03-20T040000.000Z
    reference_title: "SALL1 / Townes-Brocks syndrome 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity appears to be either haploinsufficiency or dominant-negative."
    explanation: >-
      ClinGen's curation leaves the disease mechanism open between the two
      models represented in this pathograph.
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arg276Ter) is detected in approximately half of simplex cases with TBS"
    explanation: >-
      Frequency of the recurrent hotspot variant among simplex cases.
  downstream:
  - target: Truncated SALL1 Protein Escaping Nonsense-Mediated Decay
    causal_link_type: DIRECT
- name: Truncated SALL1 Protein Escaping Nonsense-Mediated Decay
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    Despite carrying premature termination codons, the hotspot TBS alleles are
    transcribed and translated: mutant mRNA resists nonsense-mediated decay in
    patient fibroblasts, and truncated SALL1 protein is detectable in
    patient-derived cells, where it localizes to the cytoplasm. An allele that
    was NMD-susceptible was associated with a much milder phenotype, which is the
    human genetic basis for treating the stable truncated product, rather than
    reduced dosage, as the principal pathogenic species.
  genes:
  - preferred_term: SALL1
    term:
      id: hgnc:10524
      label: SALL1
  evidence:
  - reference: PMID:18000979
    reference_title: "Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In SALL1, a mutant allele causing Townes-Brocks syndrome was unexpectedly resistant to NMD, whereas a different mutation causing a much milder phenotype was susceptible to NMD."
    explanation: >-
      Allele-specific quantification in patient fibroblasts shows the TBS
      allele escapes NMD and correlates NMD susceptibility with milder disease.
  - reference: PMID:18470945
    reference_title: "SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient."
    explanation: >-
      Detects the truncated protein in patient-derived cells.
  downstream:
  - target: Dominant-Negative Interference with SALL-Family Repressors
    causal_link_type: DIRECT
  - target: Aberrant Primary Cilium Formation
    causal_link_type: DIRECT
    hypothesis_groups:
    - tbs_truncated_sall1_ciliary_dysfunction
    description: >-
      Cytoplasmic truncated SALL1 binds the ciliogenesis suppressors CCP110 and
      CEP97, a function independent of transcriptional repression.
    evidence:
    - reference: PMID:29395072
      reference_title: "Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97."
      explanation: >-
        Proximity proteomics links the truncated protein to ciliogenesis
        regulators.
- name: Dominant-Negative Interference with SALL-Family Repressors
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Wild-type SALL1 is a zinc-finger transcriptional repressor that localizes to
    pericentromeric heterochromatin and recruits the NuRD corepressor complex
    through a conserved N-terminal motif. The truncated protein retains the
    SALL-interaction and repression regions but not the DNA-binding zinc
    fingers; it interacts with all SALL family members and is proposed to
    sequester them, reducing SALL-dependent repression of developmental target
    genes. The strongest support is the Sall1 allelic series in mouse: a
    truncating allele reproduces TBS features in heterozygotes whereas a null
    allele does not. Confidence is PROVISIONAL because the dominant-negative
    model does not account for the TBS phenotype of patients with whole-gene
    SALL1 deletions (see SALL1 Haploinsufficiency).
  genes:
  - preferred_term: SALL1
    term:
      id: hgnc:10524
      label: SALL1
  biological_processes:
  - preferred_term: SALL-dependent transcriptional repression
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: DECREASED
  cellular_components:
  - preferred_term: NuRD complex
    term:
      id: GO:0016581
      label: NuRD complex
  evidence:
  - reference: PMID:12915476
    reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS."
    explanation: >-
      A mouse allele expressing a truncated Sall1 reproduces TBS, where the
      null allele does not.
  - reference: PMID:12915476
    reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins."
    explanation: >-
      Provides the sequestration mechanism underlying the dominant-negative
      model.
  - reference: PMID:18470945
    reference_title: "SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients."
    explanation: >-
      Transgenic expression of the truncated protein on a wild-type background
      is sufficient for TBS-like limb malformation, a gain-of-product result.
  - reference: PMID:16707490
    reference_title: "A conserved 12-amino acid motif in Sall1 recruits the nucleosome remodeling and deacetylase corepressor complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that endogenous Sall1 binds to the nucleosome remodeling and deacetylase corepressor complex (NuRD) and confirm the functionality of the Sall1-associating macromolecular complex by showing that the complex possesses HDAC activity."
    explanation: >-
      Establishes the NuRD corepressor recruitment that underlies Sall1
      repressor function.
  - reference: PMID:11751684
    reference_title: "SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "It was further demonstrated that SALL1 acts as a strong transcriptional repressor in mammalian cells."
    explanation: >-
      Establishes the normal repressor function that the truncated protein is
      proposed to interfere with.
  downstream:
  - target: Ectopic Derepression of SALL Target Genes
    causal_link_type: DIRECT
  - target: Impaired Metanephric Kidney Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12915476
      reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities."
      explanation: >-
        Heterozygous truncating-allele mice develop renal cystic hypoplasia.
  - target: Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cochlear developmental step affected is not characterized; the edge
      rests on the heterozygous truncating-allele mouse phenotype.
    evidence:
    - reference: PMID:12915476
      reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities."
      explanation: >-
        Heterozygous truncating-allele mice have high-frequency sensorineural
        hearing loss.
  - target: Anal Atresia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Anal malformation is seen only in mice homozygous for the truncating
      allele, not in heterozygotes, so the mouse supports that the truncated
      protein can perturb anorectal development but not the dosage at which
      this happens in heterozygous humans.
    evidence:
    - reference: PMID:12915476
      reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous sall1-DeltaZn2-10 mutant mice exhibit more severe defects than sall1-null mice including complete renal agenesis, exencephaly, limb and anal deformities."
      explanation: >-
        Anal deformity in homozygous truncating-allele mice, more severe than in
        null mice.
- name: Ectopic Derepression of SALL Target Genes
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    In mouse, the truncated protein's dominant-negative activity leads to
    ectopic activation of Sall-repressed targets, shown for Nppa in the
    developing heart and Shox2 in the developing limb. Which derepressed genes
    are responsible for which human malformations is not established; the
    cardiac Nppa finding has not been linked to the human congenital heart
    defects.
  genes:
  - preferred_term: NPPA
    term:
      id: hgnc:7939
      label: NPPA
  - preferred_term: SHOX2
    term:
      id: hgnc:10854
      label: SHOX2
  evidence:
  - reference: PMID:18470945
    reference_title: "SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb."
    explanation: >-
      Direct demonstration of target-gene derepression by the truncated
      protein in mouse embryos.
  downstream:
  - target: Disrupted Autopod Digit Patterning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18470945
      reference_title: "SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We propose a model for the pathogenesis of TBS in which truncated Sall1 protein causes derepression of Sall-responsive target genes."
      explanation: >-
        The authors' model linking target-gene derepression to the TBS
        malformations; stated as a proposal.
- name: SALL1 Whole- or Partial-Gene Deletion
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A heterozygous copy-number loss removing all or part of SALL1 (reported
    sizes from a 3.4 kb intragenic deletion to multi-megabase deletions that
    also remove neighbouring genes). Deletions are a minority of SALL1-TBS and
    are missed by sequence analysis alone, so their detection requires
    quantitative PCR, MLPA or chromosomal microarray.
  genes:
  - preferred_term: SALL1
    term:
      id: hgnc:10524
      label: SALL1
  genetic_context:
    gene:
      preferred_term: SALL1
      term:
        id: hgnc:10524
        label: SALL1
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous deletion producing no truncated product; the allele acts by
      reduced SALL1 dosage.
  evidence:
  - reference: PMID:16429401
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We applied quantitative real time PCR to detect and map SALL1 deletions in 240 patients with the clinical diagnosis of TBS, who were negative for SALL1 mutations. Deletions were found in three families."
    explanation: >-
      Identifies SALL1 deletions in three of 240 sequence-negative clinically
      diagnosed families.
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a family with autosomal dominant hearing impairment and mild anal and skeletal anomalies, in whom a novel 350 kb SALL1 deletion, spanning exon 1 and the upstream region, was identified by array comparative genomic hybridization."
    explanation: >-
      A further SALL1 deletion family detected by chromosomal microarray.
  downstream:
  - target: SALL1 Haploinsufficiency
    causal_link_type: DIRECT
- name: SALL1 Haploinsufficiency
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Loss of one SALL1 allele without a truncated product. Human deletion
    carriers have TBS, which establishes that dosage reduction alone is
    pathogenic in humans even though heterozygous Sall1-null mice have no TBS
    phenotype. The phenotype of deletion carriers has been reported as milder
    than that of truncating-variant carriers, with fewer complete triads and no
    reported congenital heart disease, but a possibly higher rate of
    developmental delay; a later review of all reported deletions and truncating
    variants did not support the milder-phenotype correlation. The
    genotype-phenotype question remains open on a small number of deletion
    families.
  genes:
  - preferred_term: SALL1
    term:
      id: hgnc:10524
      label: SALL1
  evidence:
  - reference: PMID:16429401
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results confirm that SALL1 haploinsufficiency is sufficient to cause a mild TBS phenotype but suggest that it is not sufficient to cause the severe, classical form."
    explanation: >-
      Deletion carriers establish haploinsufficiency as pathogenic and are
      reported as milder than point-mutation carriers.
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We review the clinical findings of known individuals with SALL1 deletions and point out that the overall phenotype is milder, especially when compared with individuals who carry the recurrent p.Arg276Ter mutation, but with a possible higher risk of developmental delay."
    explanation: >-
      Literature comparison of deletion carriers against p.Arg276Ter carriers.
  - reference: PMID:22308078
    reference_title: "Implications for genotype-phenotype predictions in Townes-Brocks syndrome: case report of a novel SALL1 deletion and review of the literature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, they do not support the correlation of SALL1 deletions with a milder TBS phenotype and highlight a need for more robust clinical phenotyping combined with investigation of mutational mechanism."
    explanation: >-
      Contradicts the claim that deletions produce a milder phenotype; it does
      not contradict haploinsufficiency being pathogenic.
  downstream:
  - target: Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36833185
      reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mother (II-2) had bilateral sensorineural hearing loss and asymmetrically positioned ears."
      explanation: >-
        Sensorineural hearing loss in a SALL1-deletion carrier.
  - target: Anal Stenosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36833185
      reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "71 kb SALL1 deletion was reported in a patient with bilateral sensorineural hearing impairment, anal stenosis, broad fingertips, mild global developmental delay, and penile hypospadias."
      explanation: >-
        Anal stenosis in a previously reported SALL1-deletion carrier,
        summarized in this review of deletion cases.
- name: Aberrant Primary Cilium Formation
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Truncated SALL1 binds the ciliogenesis suppressors CCP110 and CEP97 and
    promotes the proteasomal degradation of LUZP1, reducing these negative
    regulators at the mother centriole. TBS patient fibroblasts, a CRISPR model
    cell line and TBS-modelled mouse embryonic fibroblasts form primary cilia
    more frequently, with altered cilium length and disassembly and aberrant
    Sonic hedgehog signal transduction. This places TBS in phenotypic overlap
    with the ciliopathies, but the evidence is cellular and the contribution of
    ciliary dysfunction to the malformations in vivo is untested.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: INCREASED
  - preferred_term: Sonic hedgehog signal transduction
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:29395072
    reference_title: "Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls."
    explanation: >-
      Increased ciliogenesis in patient and model cells.
  - reference: PMID:29395072
    reference_title: "Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction."
    explanation: >-
      Altered cilium dynamics and Hedgehog transduction in TBS-like cells.
  - reference: PMID:32553112
    reference_title: "LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Truncated SALL1 increases the ubiquitin proteasome-mediated degradation of LUZP1."
    explanation: >-
      A second ciliary regulator depleted by the truncated protein.
  downstream:
  - target: Disrupted Autopod Digit Patterning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tbs_truncated_sall1_ciliary_dysfunction
    description: >-
      Proposed rather than demonstrated: altered ciliary Hedgehog transduction
      would perturb limb patterning, which depends on Sonic hedgehog signalling.
    evidence:
    - reference: PMID:29395072
      reference_title: "Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology."
      explanation: >-
        The authors' hypothesis linking the cellular finding to the TBS
        malformations; not tested in vivo.
- name: Impaired Metanephric Kidney Development
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Sall1 is expressed in the metanephric mesenchyme surrounding the ureteric
    bud and is required for ureteric bud invasion, the first inductive step of
    metanephric development; complete loss gives renal agenesis. In
    heterozygous truncating-allele mice kidney development is partial, giving
    cystic hypoplasia. The human counterpart is congenital renal
    hypoplasia/dysplasia, which is the usual substrate of the chronic kidney
    disease in TBS.
  cell_types:
  - preferred_term: metanephric mesenchyme stem cell
    term:
      id: CL:0000324
      label: metanephric mesenchyme stem cell
  biological_processes:
  - preferred_term: metanephros development
    term:
      id: GO:0001656
      label: metanephros development
    modifier: ABNORMAL
  - preferred_term: ureteric bud development
    term:
      id: GO:0001657
      label: ureteric bud development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:11688560
    reference_title: "Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sall1 is expressed in the metanephric mesenchyme surrounding ureteric bud; homozygous deletion of Sall1 results in an incomplete ureteric bud outgrowth, a failure of tubule formation in the mesenchyme and an apoptosis of the mesenchyme."
    explanation: >-
      Defines the developmental step that requires Sall1.
  - reference: PMID:11688560
    reference_title: "Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sall1 is therefore essential for ureteric bud invasion, the initial key step for metanephros development."
    explanation: >-
      States the conclusion that Sall1 gates metanephric induction.
  downstream:
  - target: Renal Hypoplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12915476
      reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities."
      explanation: >-
        Renal hypoplasia is the kidney outcome of the heterozygous truncating
        allele.
  - target: Polycystic Kidney Dysplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12915476
      reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities."
      explanation: >-
        The murine renal lesion is cystic as well as hypoplastic.
- name: Disrupted Autopod Digit Patterning
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  description: >-
    Abnormal specification of digit number and identity in the anterior
    (preaxial) autopod, producing thumb duplication and triphalangeal thumbs,
    with homologous foot anomalies (overlapping toes, flat feet). The radius is
    characteristically spared, which separates TBS from the radial-ray
    syndromes. The disorder-specific patterning input is the truncated SALL1
    protein; which patterning signal it perturbs is not settled, with target-gene
    derepression (Shox2) and ciliary Hedgehog transduction both proposed.
  biological_processes:
  - preferred_term: anterior/posterior pattern specification
    term:
      id: GO:0009952
      label: anterior/posterior pattern specification
    modifier: ABNORMAL
  - preferred_term: embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18470945
    reference_title: "SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients."
    explanation: >-
      Truncated SALL1 is sufficient to produce TBS-like limb malformation.
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius"
    explanation: >-
      GeneReviews describes the preaxial digit pattern and the sparing of the
      radius.
  downstream:
  - target: Preaxial Hand Polydactyly
    causal_link_type: DIRECT
  - target: Triphalangeal Thumb
    causal_link_type: DIRECT
  - target: Thumb Hypoplasia
    causal_link_type: DIRECT
  - target: Overlapping Toes
    causal_link_type: DIRECT
phenotypes:
- category: Gastrointestinal
  name: Anal Atresia
  description: >-
    Imperforate anus, often with a perineal or rectovaginal fistula, is the
    anorectal component of the classic triad and a neonatal surgical emergency.
    Anorectal malformation of any type (atresia, stenosis or anterior
    displacement) was present in two thirds of reported patients in a
    207-patient literature review; the share that is atresia is not given, so no
    frequency band is asserted for atresia alone.
  phenotype_term:
    preferred_term: Imperforate anus
    term:
      id: HP:0002023
      label: Anal atresia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears"
    explanation: GeneReviews lists imperforate anus in the defining triad.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical triad was identified in 95/191 (49.7%) of patients with dysplastic ears being the most common sign (83.5%), followed by thumb malformations (74.2%) and anorectal malformation (66.7%)."
    explanation: >-
      Anorectal malformation of any type in 66.7% of 207 reported patients.
- category: Gastrointestinal
  name: Anal Stenosis
  description: >-
    Anal stenosis is the milder anorectal presentation within the triad and is
    the anorectal finding reported in some SALL1-deletion carriers.
  phenotype_term:
    preferred_term: Anal stenosis
    term:
      id: HP:0002025
      label: Anal stenosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears"
    explanation: GeneReviews includes anal stenosis in the triad.
- category: Gastrointestinal
  name: Anteriorly Placed Anus
  description: >-
    An anteriorly (ventrally) displaced anus, a minor anorectal anomaly that can
    be the only anorectal sign in mildly affected relatives.
  phenotype_term:
    preferred_term: Anteriorly placed anus
    term:
      id: HP:0001545
      label: Anteriorly placed anus
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She presented with a ventrally positioned anus, pantonal sensorineural hearing loss (prevalent in the left ear) of mild-medium severity, and speech delay."
    explanation: Ventrally positioned anus in a SALL1-deletion proband.
  - reference: ORPHA:857
    reference_title: "Townes-Brocks syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001545 | Anteriorly placed anus | Frequent (79-30%)"
    explanation: >-
      Orphanet annotation for Townes-Brocks syndrome (parent concept); no
      frequency is asserted here because the Orphanet record is not
      SALL1-specific.
- category: Gastrointestinal
  name: Constipation
  description: >-
    Constipation requiring stool softeners, prokinetics, osmotic agents or
    laxatives. GeneReviews recommends assessing for constipation at every
    visit.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: ORPHA:857
    reference_title: "Townes-Brocks syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002019 | Constipation | Frequent (79-30%)"
    explanation: >-
      Orphanet annotation for Townes-Brocks syndrome (parent concept); no
      frequency is asserted here because the record is not SALL1-specific.
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Assess for constipation and assess growth and thyroid function at each visit"
    explanation: GeneReviews surveillance for constipation.
- category: Auditory
  name: Dysplastic Ears
  frequency: VERY_FREQUENT
  description: >-
    Dysplastic external ears, most characteristically overfolded superior
    helices ("satyr ear") and preauricular tags, occasionally microtia. The most
    common single sign in the reported literature.
  phenotype_term:
    preferred_term: Dysplastic ears
    term:
      id: HP:0000377
      label: Abnormal pinna morphology
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical triad was identified in 95/191 (49.7%) of patients with dysplastic ears being the most common sign (83.5%), followed by thumb malformations (74.2%) and anorectal malformation (66.7%)."
    explanation: >-
      Dysplastic ears in 83.5% of reported patients supports VERY_FREQUENT
      (80-100%).
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment)"
    explanation: GeneReviews description of the ear anomaly.
- category: Auditory
  name: Overfolded Helix
  description: >-
    Overfolding of the superior helix, the most characteristic TBS ear
    anomaly.
  phenotype_term:
    preferred_term: Overfolded superior helix
    term:
      id: HP:0000396
      label: Overfolded helix
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment)"
    explanation: GeneReviews names overfolded superior helices.
- category: Auditory
  name: Preauricular Skin Tag
  description: Preauricular skin tags, part of the TBS ear dysplasia.
  phenotype_term:
    preferred_term: Preauricular tag
    term:
      id: HP:0000384
      label: Preauricular skin tag
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment)"
    explanation: GeneReviews names preauricular tags.
- category: Auditory
  name: Microtia
  description: Microtia is reported among the TBS external ear anomalies.
  phenotype_term:
    preferred_term: Microtia
    term:
      id: HP:0008551
      label: Microtia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Among ear anomalies, the most typical are overfolded superior helices, preauricular tags and microtia, frequently associated with hearing impairment (sensorineural and/or conductive)."
    explanation: >-
      Introductory summary of the TBS ear phenotype in a case report; the
      observation is not this paper's own result.
- category: Auditory
  name: Hearing Impairment
  frequency: FREQUENT
  description: >-
    Hearing impairment affects about two thirds of reported patients. It is
    usually sensorineural, bilateral and mild to moderate, can be postlingual,
    and can appear at any age, which is why GeneReviews recommends annual
    audiology rather than relying on the newborn hearing screen.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, 128/197 (65.0%) of patients were diagnosed with deafness, which was often sensorineural and mild to moderate."
    explanation: >-
      65% in the literature review supports FREQUENT (30-79%).
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal failure and deafness can occur at any age, making follow-up essential."
    explanation: Hearing loss can appear at any age, supporting lifelong surveillance.
- category: Auditory
  name: Sensorineural Hearing Impairment
  description: >-
    The predominant hearing-loss type; in one series usually postlingual,
    bilateral and mild to moderate.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases, deafness was post lingual, sensorineural, bilateral, mild to moderate."
    explanation: Characterizes the hearing loss in a 49-patient series.
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while over 60% (65/108) exhibited sensorineural HL (SNHL)."
    explanation: Sensorineural loss predominates in 108 patients with hearing data.
- category: Auditory
  name: Conductive Hearing Impairment
  description: >-
    Conductive or mixed hearing loss is less common than sensorineural loss in
    TBS; middle and inner ear malformations have been documented on imaging.
  phenotype_term:
    preferred_term: Conductive or mixed hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 108 patients, 11.1% (12/108) were diagnosed with conductive HL (CHL) or mixed HL"
    explanation: >-
      11.1% conductive or mixed; the source does not separate the two, so no
      frequency band is asserted for conductive loss alone.
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient."
    explanation: Structural middle and inner ear malformation on imaging.
- category: Skeletal
  name: Preaxial Hand Polydactyly
  description: >-
    Thumb duplication (preaxial polydactyly), one of the two principal thumb
    anomalies of the triad. Thumb malformations of any type were reported in
    about three quarters of patients in the literature review; the polydactyly
    share is not given, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Preaxial polydactyly (thumb duplication)
    term:
      id: HP:0001177
      label: Preaxial hand polydactyly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thumb malformations (duplication of the thumb"
    explanation: GeneReviews lists thumb duplication among the thumb malformations.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thumb malformations were present in 53.1% with mostly triphalangeal and/or duplicated thumbs"
    explanation: >-
      In the authors' 49-patient series, thumb malformations were mostly
      triphalangeal and/or duplicated thumbs.
- category: Skeletal
  name: Triphalangeal Thumb
  description: Triphalangeal thumb, the other principal thumb anomaly of the triad.
  phenotype_term:
    preferred_term: Triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius"
    explanation: GeneReviews lists triphalangeal thumbs.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thumb malformations were present in 53.1% with mostly triphalangeal and/or duplicated thumbs"
    explanation: Triphalangeal thumb is one of the two dominant thumb anomalies.
- category: Skeletal
  name: Thumb Hypoplasia
  frequency: VERY_RARE
  description: >-
    Thumb hypoplasia is a rare TBS thumb anomaly; unlike the radial-ray
    disorders it occurs without radial hypoplasia.
  phenotype_term:
    preferred_term: Hypoplastic thumb
    term:
      id: HP:0009601
      label: Aplasia/Hypoplasia of the thumb
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius"
    explanation: GeneReviews describes thumb hypoplasia as rare, supporting VERY_RARE.
  - reference: PMID:11484202
    reference_title: "Unique family with Townes-Brocks syndrome, SALL1 mutation, and cardiac defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, hypoplastic thumbs were seen in two individuals in this family and should, therefore, be considered a true feature of TBS."
    explanation: Family report establishing thumb hypoplasia as part of TBS.
- category: Skeletal
  name: Overlapping Toes
  description: >-
    Foot malformations, mainly overlapping toes, clinodactyly of the toes and
    flat feet, the lower-limb counterpart of the preaxial hand anomalies.
    Lower-limb malformations of any type were reported in about half of
    patients in the literature review.
  phenotype_term:
    preferred_term: Overlapping toes
    term:
      id: HP:0001845
      label: Overlapping toe
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foot malformations (flat feet, overlapping toes) and genitourinary malformations are common."
    explanation: GeneReviews lists overlapping toes among common foot malformations.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lower limb malformations were mainly clinodactyly and overlapping toe"
    explanation: Overlapping toe is one of the two main lower-limb anomalies in the series.
- category: Skeletal
  name: Pes Planus
  description: Flat feet are among the common TBS foot malformations.
  phenotype_term:
    preferred_term: Flat feet
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foot malformations (flat feet, overlapping toes) and genitourinary malformations are common."
    explanation: GeneReviews lists flat feet among common foot malformations.
- category: Renal
  name: Renal Hypoplasia
  description: >-
    Congenital renal hypoplasia or hypodysplasia, the most characteristic
    structural kidney lesion of TBS, which can progress to kidney failure. Other
    reported structural anomalies include ectopic or malrotated kidneys,
    horseshoe kidney and vesicoureteral reflux. Kidney structural malformation
    of any type was reported in about 42% of patients in a literature review.
  phenotype_term:
    preferred_term: Renal hypoplasia/hypodysplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."
    explanation: GeneReviews lists renal hypoplasia among the structural anomalies.
  - reference: PMID:19204018
    reference_title: "Nephropathy in Townes-Brocks syndrome (SALL1 mutation): imaging and pathological findings in adulthood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal involvement (hypo-dysplasia, multicystic kidneys or unilateral absence) is observed in almost half of patients and may progress to end-stage renal failure in childhood."
    explanation: Renal hypodysplasia as the principal renal lesion.
  sequelae:
  - target: Chronic Kidney Disease
    evidence:
    - reference: PMID:40348827
      reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chronic renal failure occurred at any age, mostly in young adults but also in neonates (2 patients) and was often associated with hypo-dysplastic kidneys."
      explanation: Links chronic renal failure to hypodysplastic kidneys.
- category: Renal
  name: Polycystic Kidney Dysplasia
  description: Multicystic or polycystic dysplastic kidneys.
  phenotype_term:
    preferred_term: Multicystic/polycystic kidney dysplasia
    term:
      id: HP:0000113
      label: Polycystic kidney dysplasia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."
    explanation: GeneReviews lists polycystic kidneys.
  - reference: PMID:19204018
    reference_title: "Nephropathy in Townes-Brocks syndrome (SALL1 mutation): imaging and pathological findings in adulthood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal involvement (hypo-dysplasia, multicystic kidneys or unilateral absence) is observed in almost half of patients and may progress to end-stage renal failure in childhood."
    explanation: Multicystic kidneys among TBS renal lesions.
- category: Renal
  name: Horseshoe Kidney
  description: Renal fusion anomaly reported in TBS.
  phenotype_term:
    preferred_term: Horseshoe kidney
    term:
      id: HP:0000085
      label: Horseshoe kidney
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."
    explanation: GeneReviews lists horseshoe kidney.
- category: Renal
  name: Ectopic Kidney
  description: Renal ectopia and mild malrotation.
  phenotype_term:
    preferred_term: Ectopic kidney
    term:
      id: HP:0000086
      label: Ectopic kidney
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."
    explanation: GeneReviews lists ectopia.
- category: Renal
  name: Vesicoureteral Reflux
  description: >-
    Vesicoureteral reflux, which in at least one SALL1-deletion carrier led to
    reflux nephropathy and renal failure.
  phenotype_term:
    preferred_term: Vesicoureteral reflux
    term:
      id: HP:0000076
      label: Vesicoureteral reflux
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux)."
    explanation: GeneReviews lists vesicoureteral reflux.
  sequelae:
  - target: Chronic Kidney Disease
    evidence:
    - reference: PMID:36833185
      reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "vesicoureteral reflux that caused reflux nephropathy and ultimately renal failure"
      explanation: >-
        One reported SALL1-deletion carrier progressed from reflux to renal
        failure.
- category: Renal
  name: Chronic Kidney Disease
  description: >-
    Chronic kidney disease affects roughly a third of reported patients (29.3%
    in a 207-patient literature review, 39.6% in the authors' own 49-patient
    series, so no single frequency band is asserted) and can appear at any age,
    from the neonatal period to adulthood. Some patients have kidney failure
    without any structural abnormality on ultrasound, and focal segmental
    glomerulosclerosis has been found on biopsy. Kidney failure is sometimes the
    presenting feature that leads to the diagnosis in adults. This is why
    GeneReviews recommends annual monitoring of kidney function in every
    affected individual, including those with normal kidneys at first
    evaluation.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TBS-related renal impairment could present as ESRD during early childhood or progress insidiously from asymptomatic mild reduced clearance"
    explanation: >-
      Supports the PROGRESSIVE clinical course: renal impairment can progress
      insidiously from mildly reduced clearance.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney structural malformations and chronic renal failure affected 81/191 (42.4%) and 56/191 (29.3%) of patients (9.5% of which progressed to end-stage renal failure), respectively."
    explanation: Chronic renal failure in 29.3% of reported patients.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, 3 patients had chronic renal failure without abnormalities on kidney ultrasound."
    explanation: CKD can occur without detectable structural anomaly.
  - reference: PMID:17910067
    reference_title: "Kidney failure in Townes-Brocks syndrome: an under recognized phenomenon?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that kidney failure may be a constituent element of the natural history of Townes-Brocks syndrome and raise the possible benefits of longitudinal survey for progressive kidney impairment in patients with this syndrome."
    explanation: Establishes kidney failure as part of TBS natural history.
  sequelae:
  - target: Kidney Failure
    evidence:
    - reference: PMID:38296632
      reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TBS-related renal impairment could present as ESRD during early childhood or progress insidiously from asymptomatic mild reduced clearance"
      explanation: Describes progression from mild impairment to ESRD.
- category: Renal
  name: Kidney Failure
  description: >-
    End-stage kidney disease requiring dialysis or transplantation, reported
    from early childhood onwards.
  phenotype_term:
    preferred_term: End-stage kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eleven individuals were reported to get diagnosed between neonatal birth and middle childhood (0-11 years old), 3 of them had already advanced to end-stage renal disease (ESRD), necessitating dialysis or renal transplantation."
    explanation: Kidney failure already present in childhood in 3 of 11 patients.
  - reference: PMID:19204018
    reference_title: "Nephropathy in Townes-Brocks syndrome (SALL1 mutation): imaging and pathological findings in adulthood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal involvement (hypo-dysplasia, multicystic kidneys or unilateral absence) is observed in almost half of patients and may progress to end-stage renal failure in childhood."
    explanation: ESKD can be reached in childhood.
  - reference: PMID:33438842
    reference_title: "Adult diagnosis of Townes-Brocks syndrome with renal failure: Two related cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 44 adult cases of TBS with genetic confirmation (including our two cases), 10 had kidney disease."
    explanation: >-
      Kidney disease in 10 of 44 molecularly confirmed adults, from a
      literature review of adult-diagnosed TBS.
  - reference: PMID:33438842
    reference_title: "Adult diagnosis of Townes-Brocks syndrome with renal failure: Two related cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age of kidney disease diagnosis was 30 years old and of renal transplant 49 years old."
    explanation: >-
      Kidney failure also arises in adulthood, supporting lifelong kidney
      surveillance beyond the pediatric period.
- category: Renal
  name: Focal Segmental Glomerulosclerosis
  description: >-
    FSGS has been found on kidney biopsy in TBS patients with chronic kidney
    disease; whether it is a primary podocyte lesion or secondary to reduced
    nephron mass is not established.
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - reference: PMID:19204018
    reference_title: "Nephropathy in Townes-Brocks syndrome (SALL1 mutation): imaging and pathological findings in adulthood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both exhibited severe chronic renal failure and kidney hypodysplasia by imaging studies while focal and segmental glomerulosclerosis (FSGS) was demonstrated in one case."
    explanation: FSGS on biopsy in an adult TBS patient.
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Genital anomalies affect about a quarter of affected males, including
    cryptorchidism, hypospadias and bifid scrotum; vaginal aplasia with bifid
    uterus is reported in females.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:16088922
    reference_title: "SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare phenotypical features among mutation positive patients include hypothyroidism, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, dorsal hypoplasia of the corpus callosum, and umbilical hernia."
    explanation: Cryptorchidism in SALL1 mutation-positive patients.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A genital anomaly was observed in 24/96 (25%) of males and in only 3/93 (3.23%) of females."
    explanation: >-
      Genital anomalies of any type in 25% of males; the review does not give
      the cryptorchidism share, so no frequency is asserted.
- category: Genitourinary
  name: Hypospadias
  description: Hypospadias, reported among the male genital anomalies.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "71 kb SALL1 deletion was reported in a patient with bilateral sensorineural hearing impairment, anal stenosis, broad fingertips, mild global developmental delay, and penile hypospadias."
    explanation: Penile hypospadias in a SALL1-deletion carrier.
- category: Cardiovascular
  name: Congenital Heart Defect
  frequency: OCCASIONAL
  description: >-
    Congenital heart disease in about 15-20% of patients, ranging from septal
    defects to tetralogy of Fallot and, in one family, lethal truncus
    arteriosus and pulmonary valve atresia. It has been reported more often
    with the recurrent p.Arg276Ter variant. No mechanism linking SALL1 to the
    heart defects is established in this entry.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart disease occurs in 15% of affected individuals."
    explanation: 15% supports OCCASIONAL (5-29%).
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly 19% (37/196) of individuals had congenital heart defect."
    explanation: 19% in the literature review, also within OCCASIONAL.
  - reference: PMID:11484202
    reference_title: "Unique family with Townes-Brocks syndrome, SALL1 mutation, and cardiac defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unique cardiac anomalies seen in this family include lethal truncus arteriosus in one patient and a lethal complicated defect, including pulmonary valve atresia, in a second patient."
    explanation: Severe conotruncal and valvular defects in a TBS family.
  - reference: PMID:11484202
    reference_title: "Unique family with Townes-Brocks syndrome, SALL1 mutation, and cardiac defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This family and a review of the literature indicate that cardiac evaluation is warranted in all individuals with this disorder."
    explanation: Basis for cardiac evaluation of every affected individual.
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show a slight increase in congenital anomalies in patients with p.Arg276Ter, which is significant only for ear anomalies and congenital heart defects."
    explanation: Association of congenital heart defects with p.Arg276Ter.
- category: Cardiovascular
  name: Tetralogy of Fallot
  description: One of the specific congenital heart defects reported in TBS.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "congenital heart defects (tetralogy of Fallot and ventricular septal defects)"
    explanation: >-
      Introductory summary of reported TBS heart defects in a case report, not
      the paper's own finding.
- category: Neurological
  name: Developmental Delay
  frequency: OCCASIONAL
  description: >-
    Developmental delay and/or learning difficulty in roughly 8-15% of
    patients, usually mild; GeneReviews recommends annual developmental and
    educational assessment. A possibly higher rate among SALL1-deletion
    carriers has been suggested on few cases.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and/or learning difficulties occur in approximately 15% of affected individuals."
    explanation: 15% supports OCCASIONAL (5-29%).
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We undertook a review of patients with DD and/or ID and found a proportion of 8% (14/175) having DD/ID"
    explanation: 8% in the literature review, within OCCASIONAL.
- category: Endocrine
  name: Hypothyroidism
  description: >-
    Hypothyroidism, sometimes subclinical, in about 5% of reported patients.
    GeneReviews recommends checking thyroid function at each visit.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endocrinological features were present in 28/196 (14.3%) of patients with 5.6% having hypothyroidism and 4% having growth retardation."
    explanation: Hypothyroidism in 5.6% of reported patients.
  - reference: PMID:38296632
    reference_title: "Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By comprehensive clinical evaluations, we further provide evidence for the causal relationship between SALL1 variation and certain endocrine abnormalities."
    explanation: Family segregation data supporting endocrine involvement.
- category: Endocrine
  name: Growth Hormone Deficiency
  description: >-
    Growth hormone deficiency has been reported and is treated with growth
    hormone.
  phenotype_term:
    preferred_term: Growth hormone deficiency
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  evidence:
  - reference: PMID:23894113
    reference_title: "Endocrine abnormalities in Townes-Brocks syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 1 appears to be the first known case of growth hormone deficiency, and Patient 2 extends the number of documented mutation cases with hypothyroidism to four."
    explanation: Growth hormone deficiency in a molecularly confirmed patient.
- category: Growth
  name: Growth Delay
  description: >-
    Growth deficiency is a rare feature of TBS; growth should be assessed at
    every visit.
  phenotype_term:
    preferred_term: Growth deficiency
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."
    explanation: GeneReviews lists growth deficiency as rare.
- category: Ophthalmologic
  name: Duane Anomaly
  description: >-
    Duane anomaly, part of a broader spectrum of congenital cranial
    dysinnervation reported in TBS (Moebius sequence, Marcus Gunn jaw winking,
    gustatory lacrimation).
  phenotype_term:
    preferred_term: Duane anomaly
    term:
      id: HP:0009921
      label: Duane anomaly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."
    explanation: GeneReviews lists Duane anomaly as rare.
  - reference: PMID:31981611
    reference_title: "Ocular features of Townes-Brocks syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmic findings have been rarely reported and include congenital cataract, microphthalmia, optic nerve atrophy, coloboma, epibulbar dermoid, and dysinnervation patterns, such as Duane syndrome and gustatory lacrimation."
    explanation: Summarizes the reported ocular spectrum including Duane syndrome.
- category: Ophthalmologic
  name: Iris Coloboma
  description: Rare ocular feature; chorioretinal coloboma is also reported.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."
    explanation: GeneReviews lists iris coloboma as rare.
- category: Ophthalmologic
  name: Congenital Cataract
  description: Congenital cataract, reported with unilateral microphthalmia.
  phenotype_term:
    preferred_term: Congenital cataract
    term:
      id: HP:0000519
      label: Developmental cataract
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:17221874
    reference_title: "Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia."
    explanation: First report of congenital cataract in SALL1-TBS.
- category: Ophthalmologic
  name: Microphthalmia
  description: Unilateral microphthalmia, reported with congenital cataract.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:17221874
    reference_title: "Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia."
    explanation: Microphthalmia in SALL1-TBS.
- category: Neurological
  name: Chiari Type I Malformation
  description: Rare feature of TBS.
  phenotype_term:
    preferred_term: Chiari I malformation
    term:
      id: HP:0007099
      label: Chiari type I malformation
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation."
    explanation: GeneReviews lists Chiari I malformation as rare.
genetic:
- name: SALL1
  gene_term:
    preferred_term: SALL1
    term:
      id: hgnc:10524
      label: SALL1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    SALL1 at 16q12.1 is the only gene for TBS1. Pathogenic alleles are
    predominantly nonsense and frameshift variants in the exon 2 hotspot, with
    the recurrent c.826C>T (p.Arg276Ter) the most frequent single variant;
    whole- and partial-gene deletions are a minority and need a copy-number
    assay. Variants located downstream of the glutamine-rich region were
    associated in one analysis with more deafness, dysplastic ear and thumb
    malformation and less renal failure than upstream variants, though the
    downstream-variant group was significantly younger.
  evidence:
  - reference: CGGV:assertion_5883adb4-8c1e-46f0-8b23-1dd060763166-2026-03-20T040000.000Z
    reference_title: "SALL1 / Townes-Brocks syndrome 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SALL1 | HGNC:10524 | Townes-Brocks syndrome 1 | MONDO:0054581 | AD | Definitive"
    explanation: ClinGen Definitive gene-disease validity.
  - reference: PMID:9973281
    reference_title: "Molecular analysis of SALL1 mutations in Townes-Brocks syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains."
    explanation: Early mutation series establishing the truncating pattern.
  - reference: PMID:40348827
    reference_title: "Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A significant increase in deafness, dysplastic ear, and thumb malformations and a significant decrease in renal failure were observed in the individuals carrying a variant located downstream of the region, but the patients were significantly younger."
    explanation: >-
      Genotype-phenotype association by variant position, with the age
      confounder the authors note.
diagnosis:
- name: Clinical and molecular diagnosis of SALL1-TBS
  description: >-
    Suspected in a child with an anorectal malformation, dysplastic ears or
    hearing loss, and preaxial thumb anomalies with a normal radius, and
    increasingly in children and adults ascertained through hearing-loss or
    kidney-disease gene panels with incomplete or atypical features. Confirmed
    by a heterozygous pathogenic SALL1 variant. Because deletions are missed by
    sequencing, a sequencing-negative patient with a suggestive phenotype should
    have copy-number analysis.
  notes: >-
    Kidney-gene-panel cohorts identify SALL1 variants in patients whose
    presentation is non-syndromic CAKUT or a branchio-oto-renal-like
    combination of ear anomalies, hearing loss and CAKUT, sometimes first
    diagnosed in adolescence or adulthood.
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of SALL1-TBS is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in SALL1 identified by molecular genetic testing."
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:36833185
    reference_title: "Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromosomal microarray analysis is still a valuable tool in the identification of atypical/mild TBS cases, which are likely underestimated."
    explanation: Supports copy-number testing for deletions.
  - reference: PMID:40658219
    reference_title: "Clinical characteristics of patients with SALL1-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some cases present with atypical features overlapping with TBS BOR-like syndrome or isolated CAKUT, rather than with typical TBS1."
    explanation: Atypical presentations ascertained through a CKD cohort.
differential_diagnoses:
- name: Townes-Brocks Syndrome 2
  disease_term:
    preferred_term: Townes-Brocks syndrome 2
    term:
      id: MONDO:0054582
      label: Townes-Brocks syndrome 2
  description: >-
    DACT1-related autosomal dominant syndrome with imperforate anus, renal,
    genitourinary and ear anomalies overlapping TBS.
  distinguishing_features:
  - Heterozygous DACT1 rather than SALL1 variant.
  - Thumb malformations were not part of the phenotype in the first reported DACT1 family.
  evidence:
  - reference: PMID:28054444
    reference_title: "Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies."
    explanation: The DACT1 family phenotype, which lists no thumb anomaly.
- name: EYA1-Related Branchiootorenal Spectrum
  disease_term:
    preferred_term: branchiootorenal syndrome 1
    term:
      id: MONDO:0007236
      label: branchiootorenal syndrome 1
  description: >-
    Ear anomalies, hearing loss and CAKUT overlap the TBS BOR-like presentation
    of SALL1 disease.
  distinguishing_features:
  - Branchial cleft cysts or fistulae and preauricular pits favor the branchiootorenal spectrum.
  - Anorectal and thumb malformations favor SALL1.
  evidence:
  - reference: PMID:40658219
    reference_title: "Clinical characteristics of patients with SALL1-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients present only with dysplastic ears and hearing loss (HL) or with congenital anomalies of the kidney and urinary tract (CAKUT), resembling branchio-oto-renal syndrome (BORS), a presentation referred to as Townes-Brocks branchio-oto-renal-like (TBS BOR-like) syndrome."
    explanation: Describes the BOR-like SALL1 presentation that overlaps this differential.
- name: Craniofacial Microsomia
  disease_term:
    preferred_term: Goldenhar syndrome / oculoauriculovertebral spectrum
    term:
      id: MONDO:0015397
      label: craniofacial microsomia
  description: >-
    Ear anomalies and preauricular tags can make SALL1 disease resemble
    Goldenhar syndrome.
  distinguishing_features:
  - Anorectal malformation and triphalangeal or duplicated thumbs point to SALL1.
  evidence:
  - reference: PMID:9973281
    reference_title: "Molecular analysis of SALL1 mutations in Townes-Brocks syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome."
    explanation: SALL1 disease can mimic Goldenhar syndrome.
- name: VACTERL Association
  disease_term:
    preferred_term: VACTERL association
    term:
      id: MONDO:0008642
      label: VACTERL/vater association
  description: >-
    Anorectal, renal, limb and cardiac anomalies overlap VACTERL, and TBS is
    thought to be under-recognized among patients labelled as VACTERL.
  distinguishing_features:
  - Dysplastic ears and sensorineural hearing loss point to SALL1.
  - Radial hypoplasia and vertebral and tracheoesophageal anomalies favor VACTERL.
  evidence:
  - reference: PMID:23894113
    reference_title: "Endocrine abnormalities in Townes-Brocks syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "but is probably much higher due to common shared characteristics with VATER association and subtle variable phenotypes in many TBS patients"
    explanation: Introductory statement on overlap with VATER association.
- name: SALL4-Related Duane-Radial Ray Syndrome
  disease_term:
    preferred_term: Duane-radial ray syndrome (Okihiro syndrome)
    term:
      id: MONDO:0011812
      label: Duane-radial ray syndrome
  description: >-
    The paralogous SALL4 gene causes Duane anomaly with radial ray
    malformations that include triphalangeal and duplicated thumbs, and (as
    acro-renal-ocular syndrome) renal anomalies and coloboma, overlapping the
    thumb, kidney and ocular features of SALL1-TBS.
  distinguishing_features:
  - Hypoplasia or aplasia of the radius and forearm shortening favor SALL4; TBS thumb anomalies occur without radial hypoplasia.
  - Anorectal malformation and dysplastic ears with hearing loss point to SALL1.
  evidence:
  - reference: PMID:20301547
    reference_title: "SALL4-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly)."
    explanation: >-
      GeneReviews SALL4 chapter describes the overlapping thumb anomalies
      together with the radial involvement that separates DRRS from TBS.
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius"
    explanation: GeneReviews SALL1 chapter states the radius is spared in TBS.
- name: Fanconi Anemia
  disease_term:
    preferred_term: Fanconi anemia
    term:
      id: MONDO:0019391
      label: Fanconi anemia
  description: >-
    Fanconi anemia can present with thumb anomalies and a TBS-like
    malformation pattern; a chromosome breakage test or FA gene testing
    separates them.
  distinguishing_features:
  - Radial hypoplasia, skin pigmentary changes, bone marrow failure and chromosome fragility favor Fanconi anemia.
  - TBS thumb anomalies occur without radial hypoplasia.
  evidence:
  - reference: PMID:19622403
    reference_title: "Fanconi anemia and its diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FA patients may also present with a phenotype characteristic of Seckel syndrome, Nijmegen breakage syndrome, Dubowitz syndrome, Holt-Oram syndrome, thrombocytopenia absent radius (TAR) syndrome, Townes-Brocks syndrome"
    explanation: A Fanconi anemia review naming TBS among FA phenocopies.
treatments:
- name: Surgical Repair of Anorectal Malformation
  description: >-
    Immediate neonatal surgical management of imperforate anus, followed by
    bowel management for constipation (stool softeners, prokinetics, osmotic
    agents or laxatives).
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: anorectal malformation repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Imperforate anus
    term:
      id: HP:0002023
      label: Anal atresia
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immediate surgical intervention for imperforate anus; stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation"
    explanation: GeneReviews treatment of manifestations.
- name: Surgery for Severe Hand Malformations
  description: Surgical correction of severe thumb malformations.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hand surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Preaxial hand polydactyly
    term:
      id: HP:0001177
      label: Preaxial hand polydactyly
  - preferred_term: Triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "surgery for severe malformations of the hands"
    explanation: GeneReviews treatment of manifestations.
- name: Hearing Surveillance and Early Treatment of Hearing Loss
  description: >-
    Annual audiology evaluation, with early treatment of hearing loss when
    identified. Because hearing loss can be postlingual and appear at any age,
    surveillance continues after a normal newborn screen. Medications with
    otic toxicity should be avoided.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: annual audiology evaluation
    term:
      id: NCIT:C38036
      label: Audiometric Test
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual audiology evaluation; monitor kidney function annually in individuals with and without kidney anomalies, even if kidney function is normal on initial examination"
    explanation: GeneReviews surveillance recommendation for hearing and kidneys.
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Medications that cause renal or otic toxicity."
    explanation: GeneReviews agents to avoid.
- name: Lifelong Kidney Function Surveillance
  description: >-
    Annual monitoring of kidney function in every affected individual, including
    those with structurally normal kidneys and normal function at first
    evaluation, because CKD can develop at any age. Nephrotoxic medications
    should be avoided. At-risk relatives should have their genetic status
    clarified so that kidney disease can be detected early.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: annual kidney function testing
    term:
      id: NCIT:C74972
      label: Renal Function Test
  target_phenotypes:
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "annual audiology evaluation; monitor kidney function annually in individuals with and without kidney anomalies, even if kidney function is normal on initial examination"
    explanation: GeneReviews annual kidney function surveillance.
  - reference: PMID:19204018
    reference_title: "Nephropathy in Townes-Brocks syndrome (SALL1 mutation): imaging and pathological findings in adulthood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular assessment of glomerular filtration rate is mandatory throughout life in all TBS patients."
    explanation: Recommendation from adult-onset kidney failure cases.
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with SALL1-TBS in order to identify as early as possible those who would benefit from clinical evaluation and prompt initiation of treatment for kidney disease and other features of SALL1-TBS."
    explanation: GeneReviews cascade evaluation of relatives.
- name: Hemodialysis
  description: Hemodialysis for end-stage kidney disease.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  target_phenotypes:
  - preferred_term: End-stage kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hemodialysis and possibly kidney transplantation for ESKD"
    explanation: GeneReviews treatment for ESKD.
- name: Kidney Transplantation
  description: Kidney transplantation for end-stage kidney disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  target_phenotypes:
  - preferred_term: End-stage kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hemodialysis and possibly kidney transplantation for ESKD"
    explanation: GeneReviews treatment for ESKD.
- name: Growth Hormone Therapy
  description: >-
    Growth hormone for those with documented growth hormone deficiency; growth
    and thyroid function are assessed at each visit.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: CHEBI:749556
        label: somatropin
  target_phenotypes:
  - preferred_term: Growth hormone deficiency
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth hormone therapy for those with growth hormone deficiency"
    explanation: GeneReviews treatment of manifestations.
- name: Cardiac Management of Congenital Heart Defects
  description: >-
    Surgical or medical treatment of congenital heart defects under a
    cardiologist, following cardiac evaluation at diagnosis.
  treatment_term:
    preferred_term: surgical or medical cardiac treatment
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_phenotypes:
  - preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "surgery or medical treatment by cardiologist for congenital heart defects"
    explanation: GeneReviews treatment of manifestations for congenital heart defects.
- name: Genetic Counseling
  description: >-
    Autosomal dominant counseling with a 50% recurrence risk to offspring of an
    affected person; evaluation of at-risk relatives; prenatal and
    preimplantation testing once the familial variant is known, and prenatal
    cardiac and nephrology evaluation in affected pregnant women.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the SALL1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
    explanation: GeneReviews genetic counseling.
  - reference: PMID:20301618
    reference_title: "SALL1-Related Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pregnancy management: Consider prenatal cardiac and nephrology evaluations in pregnant women with SALL1-TBS."
    explanation: GeneReviews pregnancy management.
animal_models:
- name: Sall1 truncating-allele mouse (Sall1-DeltaZn2-10)
  species: Mouse
  genotype: Sall1 DeltaZn2-10 (heterozygous and homozygous)
  publication: PMID:12915476
  description: >-
    Knock-in allele expressing a truncated Sall1 that lacks zinc fingers 2-10,
    designed to mimic human TBS truncating alleles. Also used, as Sall1TBS, to
    study adult kidney injury.
  modeled_mechanisms:
  - target: Dominant-Negative Interference with SALL-Family Repressors
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Heterozygotes reproduce hearing loss, renal cystic hypoplasia and wrist
      bone anomalies, which the null allele does not.
    limitations: >-
      Heterozygotes do not show the anorectal or thumb anomalies that define
      human TBS; anal deformity appears only in homozygotes. The allele is a
      mouse-designed truncation rather than a human hotspot variant.
    readouts:
    - name: TBS-like phenotype in heterozygotes
      target: Dominant-Negative Interference with SALL-Family Repressors
      direction: ALTERED
      interpretation: Presence of hearing, renal and wrist phenotypes with one truncating allele.
      evidence:
      - reference: PMID:12915476
        reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities."
        explanation: Reports the heterozygous phenotype.
    evidence:
    - reference: PMID:12915476
      reference_title: "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS."
      explanation: The model was built to test the dominant-negative hypothesis.
  - target: Chronic Kidney Disease
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Sall1TBS mice develop slowly progressive chronic kidney disease.
    limitations: >-
      The same mice are protected from acute kidney injury, which has no known
      human counterpart; the relation of the murine CKD to the human FSGS and
      hypodysplasia findings is not established.
    evidence:
    - reference: PMID:26311113
      reference_title: "A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1TBS mice."
      explanation: Documents CKD in the truncating-allele model.
- name: Sall1 null mouse
  species: Mouse
  genotype: Sall1 null (heterozygous and homozygous)
  publication: PMID:11688560
  description: >-
    Targeted Sall1 deletion. Homozygotes die perinatally with kidney agenesis
    or severe dysgenesis; heterozygotes have no TBS-like phenotype.
  modeled_mechanisms:
  - target: Impaired Metanephric Kidney Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygous loss identifies ureteric bud invasion as the Sall1-dependent
      step of metanephric development.
    limitations: >-
      Homozygous agenesis is far more severe than the human heterozygous
      hypodysplasia spectrum.
    evidence:
    - reference: PMID:11688560
      reference_title: "Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We have isolated a mouse homolog of SALL1 (Sall1) and found that mice deficient in Sall1 die in the perinatal period and that kidney agenesis or severe dysgenesis are present."
      explanation: Homozygous null kidney phenotype.
  - target: SALL1 Haploinsufficiency
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Heterozygous Sall1-null mice lack a TBS-like phenotype, whereas humans
      with SALL1 deletions have TBS.
    limitations: >-
      Species difference in SALL1 dosage sensitivity; the mouse cannot be used
      to model the human deletion phenotype.
    evidence:
    - reference: PMID:16429401
      reference_title: "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."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "This assumption was strongly contradicted by a Sall1 mouse knock-out, because neither hetero- nor homozygous knock-out mutants displayed a TBS-like phenotype."
      explanation: >-
        The heterozygous knockout has no TBS-like phenotype; quoted from the
        background of a human deletion study.
    - reference: PMID:16429401
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It therefore seems that there is a different contribution of SALL1 gene function to mouse and human embryonic development."
      explanation: The authors' interpretation of the human/mouse discordance.
mechanistic_hypotheses:
- hypothesis_group_id: tbs_truncated_sall1_ciliary_dysfunction
  hypothesis_label: Truncated SALL1 causes TBS malformations partly through primary cilium dysfunction
  status: EMERGING
  description: >-
    Cytoplasmic truncated SALL1 binds CCP110 and CEP97 and destabilizes LUZP1,
    increasing ciliogenesis and altering Sonic hedgehog transduction; the
    hypothesis is that this transcription-independent activity contributes to
    the limb and other malformations. Supported by patient fibroblasts and
    model cell lines; not tested in vivo.
  evidence:
  - reference: PMID:29395072
    reference_title: "Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity."
    explanation: States the hypothesis tested in cellular models.
discussions:
- discussion_id: mismatch_sall1_null_heterozygote
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#SALL1 Haploinsufficiency
  - pathophysiology#Dominant-Negative Interference with SALL-Family Repressors
  prompt: >-
    Why do humans with a heterozygous SALL1 deletion have Townes-Brocks
    syndrome when heterozygous Sall1-null mice have no TBS-like phenotype?
  rationale: >-
    The dominant-negative model rests largely on the contrast between the mouse
    null allele (no phenotype in heterozygotes) and the mouse truncating allele
    (TBS-like heterozygotes). Human deletion carriers show that halving SALL1
    dosage is itself pathogenic in humans, so the mouse overstates how cleanly
    the two mechanisms separate. Whether human deletion carriers are genuinely
    milder is also disputed on few families. Until this is resolved the entry
    carries both mechanisms as PROVISIONAL.
  proposed_experiments:
  - experiment_id: exp_sall1_isogenic_ipsc_allelic_series
    name: Isogenic human iPSC SALL1 allelic series in kidney organoids
    description: >-
      Compare heterozygous SALL1 deletion, hotspot truncating (p.Arg276Ter)
      and wild-type isogenic iPSC lines differentiated into kidney organoids
      for nephron progenitor maintenance and nephron number, testing in human
      cells whether a truncating allele is more damaging than a null allele.
  - experiment_id: exp_sall1_deletion_phenotype_registry
    name: Standardized phenotyping of SALL1 deletion carriers
    description: >-
      Collect uniformly phenotyped deletion carriers (renal imaging, audiology,
      cardiac and developmental assessment) and compare against age-matched
      hotspot-variant carriers to settle the milder-phenotype question.
- discussion_id: gap_ckd_structurally_normal_kidneys
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Chronic Kidney Disease
  - pathophysiology#Impaired Metanephric Kidney Development
  prompt: >-
    What causes chronic kidney disease in TBS patients whose kidneys appear
    structurally normal on ultrasound?
  rationale: >-
    Most TBS kidney failure is attributed to congenital hypodysplasia, but
    kidney failure without an ultrasound abnormality is reported and FSGS has
    been found on biopsy. Reduced nephron endowment below the resolution of
    ultrasound, a role for SALL1 in the mature kidney (Sall1 is expressed in
    terminally differentiated renal epithelia in adult mouse), or both are
    possible. The answer determines whether kidney surveillance could be
    tailored by imaging or must remain universal.
  proposed_experiments:
  - experiment_id: exp_sall1_nephron_number_imaging
    name: Nephron number estimation in TBS patients with normal kidney ultrasound
    description: >-
      Estimate nephron number (e.g. MRI-based or biopsy-based methods) and
      follow eGFR and proteinuria longitudinally in molecularly confirmed
      patients without structural anomalies.
notes: >-
  LUMP/SPLIT DECISION. This entry is a Disease entry for SALL1-related
  Townes-Brocks syndrome (TBS1, MONDO:0054581) and not an entry for the parent
  concept Townes-Brocks syndrome (MONDO:0007142). The parent has two children in
  MONDO, TBS1 (SALL1) and TBS2 (DACT1, MONDO:0054582). They were not lumped
  because the causal lesion differs: SALL1 disease is driven by a truncated
  spalt-family transcriptional repressor (with a disputed haploinsufficiency
  contribution), whereas DACT1 encodes a Wnt-pathway antagonist, so one
  pathograph would need two unrelated trigger chains. The first reported DACT1
  family also lacked thumb anomalies. The GeneReviews chapter is itself scoped
  to SALL1 ("SALL1-Related Townes-Brocks Syndrome"), ClinGen curates SALL1
  against MONDO:0054581, and MONDO models the two as separate children. A
  has_subtypes entry on a parent Townes-Brocks Disease was not chosen because
  there is no shared mechanism for such a parent to carry. If TBS2 is curated
  later, a Grouping over both entries mapped to MONDO:0007142 would record the
  shared clinical definition. TBS BOR-like presentations and non-syndromic CAKUT
  caused by SALL1 are treated as part of this entry's phenotypic range, not as
  separate entries, because they arise from the same SALL1 alleles.

  STRUCTURED SOURCES. Orphanet ORPHA:857 is the parent Townes-Brocks syndrome
  record and lists both SALL1 and DACT1, so its phenotype annotations are cited
  only for presence, not as frequency evidence for SALL1-TBS. Frequency bands in
  this entry come from GeneReviews and from the 207-patient SALL1 literature
  review (PMID:40348827). The ClinGen gene-disease validity record is
  SALL1-specific and classifies the relationship as Definitive.

  MECHANISM. The pathograph carries two trigger chains for the two allele
  classes (truncating variants and deletions) because the literature has not
  settled the dominant-negative versus haploinsufficiency question; both
  central nodes are PROVISIONAL, and the human/mouse discordance is recorded as
  a HUMAN_MODEL_MISMATCH discussion. The ciliary mechanism is recorded as an
  EMERGING hypothesis. No mechanism for the congenital heart defects, the
  external ear dysplasia, or the endocrine and ocular features was found in the
  sources used, so those phenotypes are not connected to a mechanism node.

  PEDIATRIC SURVEILLANCE (GeneReviews, PMID:20301618). Constipation, growth and
  thyroid function at each visit; annual audiology; annual kidney function even
  with normal kidneys and normal initial function; annual developmental,
  educational and behavioral assessment; ophthalmology per ophthalmologist.
  Cardiac evaluation of every affected individual is recommended from a family
  series (PMID:11484202). Avoid nephrotoxic and ototoxic medications.

📚

References & Deep Research

References

2

PMID:20301547

SALL4-Related Disorders.

No top-level findings curated for this source.

PMID:20301618

SALL1-Related Townes-Brocks Syndrome.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review round 1: reference titles, GeneReviews tag, CKD course, cardiac treatment · 2026-09-23T15:37:30Z · View source

Response to ai4c-reviewer CHANGES_REQUESTED review 5293019794 on PR 12598. Blocking items: (1) reference_title backfilled from references_cache frontmatter on all 143 evidence items with just backfill-reference-titles; just check-reference-titles passes. (2) The SALL4 GeneReviews chapter PMID:20301547, cited for the Duane-radial ray differential, is now tagged GeneReviews in references: via just tag-references; just check-genereviews reports both chapters tagged and no CITED_UNTAGGED. Suggestions taken: clinical_course PROGRESSIVE on the Chronic Kidney Disease phenotype, with PMID:38296632 quoted ('progress insidiously from asymptomatic mild reduced clearance'); a Cardiac Management of Congenital Heart Defects treatment (NCIT:C49236 Therapeutic Procedure) targeting the congenital heart defect phenotype, quoting the GeneReviews management sentence; the GeneReviews 50% transmission sentence added as an inheritance evidence item. Suggestions declined: PROGRESSIVE on hearing loss, because the cited sources say hearing loss can appear at any age and is often postlingual, but none of the cached text states that it progresses; surveillance items were left under treatments, as the reviewer said was acceptable. Reference caches: of nine uncited cache files, all were written when the deep-research report's own citations were resolved. Seven were removed from the PR (PMID_15172686, PMID_26511275, PMID_38386912, PMID_41499068, and three DOI files that duplicate PMIDs the entry cites under their PMID). Two were kept: PMID_14627694 and PMID_9072124, which the report cites by PMID for claims that were deliberately not curated; their caches show no abstract, which is the stated reason those claims were left out. Validation: just validate, count-verified-snippets (143/143), validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-reference-titles, list-gene-term-mismatches, check-genereviews and validate-disorders all passed.

Create: Townes-Brocks_Syndrome_1 · 2026-09-23T15:17:46Z · View source

New Disease entry for SALL1-related Townes-Brocks syndrome 1 (MONDO:0054581), curated from the claim in issue 12584. Lump/split: curated as its own Disease entry rather than as the parent Townes-Brocks syndrome (MONDO:0007142) or a has_subtypes row on it. The parent's other child, TBS2 (DACT1, MONDO:0054582), has a different causal gene and pathway, so a lumped entry would carry two unrelated trigger chains. GeneReviews (PMID:20301618) is SALL1-scoped and ClinGen curates SALL1 against MONDO:0054581. TBS2 is listed as a differential. Deep research: exactly one report. falcon was requested and returned HTTP 402 (out of credits). A first attempt with the generic fallback started openscientist, but its parent recipe was terminated by SIGTERM before any report was written, and the orphaned client process was then stopped. Per the updated run brief, the report was then produced with the claude_code fallback: research/Townes-Brocks_Syndrome_1-deep-research-claude_code.md (fell_back: true, requested_provider: falcon). Reference validation: 19/19 resolved, 0 off topic. Term validation needs_review: true (HP:0002251 given for imperforate anus is Aganglionic megacolon; UBERON:0004907 and UBERON:0002544 mislabelled; GO:0005720 obsolete); none of the report's CURIEs were copied into the entry. just preflight-dr: PASS (SALL1 mentioned 59 times, OMIM 107480 matches). Report claims not carried into the entry because the cited source had no abstract in the cache: the ~50% congenital heart disease rate in p.Arg276Ter carriers (PMID:14627694, no abstract), germline mosaicism in 4 families (no citation), end-stage renal failure presentation (PMID:9072124, no abstract). Structured sources: ClinGen CGGV assertion 5883adb4 (Definitive, AD; mechanism recorded as haploinsufficiency or dominant-negative) cached from the current ClinGen CSV via the structured-source CLI with --cache-dir in the worktree; the pinned MANIFEST was not repinned. ORPHA:857 built from a scratchpad copy of the current Orphadata XML; it is the parent-concept record (SALL1 and DACT1), so its phenotype rows are cited for presence only. Most evidence was found by direct PubMed search and read from the cached abstracts or full text. Frequency bands come from GeneReviews and the 207-patient literature review in PMID:40348827. The dominant-negative versus haploinsufficiency question is modelled as two trigger chains, both PROVISIONAL, with a HUMAN_MODEL_MISMATCH discussion. The primary-cilium mechanism (PMID:29395072, PMID:32553112) is an EMERGING hypothesis group. Validation: just validate, just count-verified-snippets (140/140), just validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-reference-titles, list-gene-term-mismatches (0 findings), check-genereviews --online (TAGGED PMID:20301618) all passed; just validate-disorders run before push.

Claude Code ▸

Townes-Brocks Syndrome 1 (TBS1) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 27 citations 2026-09-23T15:05:50.437623

Townes-Brocks Syndrome 1 (TBS1) — Comprehensive Research Report

1. Disease Information

Overview. Townes-Brocks syndrome 1 (TBS1) is a rare, autosomal dominant multiple-congenital-anomaly disorder classically defined by a triad of imperforate anus/anal stenosis, dysplastic external ears, and thumb malformations (preaxial polydactyly and/or triphalangeal thumbs), caused by heterozygous pathogenic variants in SALL1 (16q12.1). It was first delineated by Townes and Brocks in 1972 and molecularly linked to SALL1 by Kohlhase et al. in 1998 (Nat Genet 18:81–83) [PMID not separately retrieved but DOI 10.1038/ng0198-81 confirmed]. Expressivity is markedly variable — from an isolated ear/hearing phenotype to severe multiorgan disease including progressive kidney failure — while penetrance is reported as essentially complete once the mild end of the spectrum is included.

Key identifiers: - OMIM: #107480 (Townes-Brocks syndrome 1); gene locus 602218 SALL1 - Orphanet: ORPHA857 - MONDO: MONDO:0054581 (per task); note a distinct Townes-Brocks syndrome 2 (TBS2), caused by biallelic/dominant DACT1 variants, lacks thumb anomalies and is a genetically and clinically separate entry (dismech CLAUDE.md's lump/split guidance applies — do not conflate TBS1/SALL1 with TBS2/DACT1) - MeSH: D054970 (Townes-Brocks Syndrome) - ICD-10/11: No dedicated code; typically coded under Q87.8 (other specified congenital malformation syndromes) - Gene/HGNC:* SALL1, hgnc:10524

Synonyms: Townes-Brocks syndrome; TBS; Townes syndrome; Imperforate anus with hand, foot, and ear anomalies; Renal-ear-anal-radial (REAR) syndrome (older, less accurate label given absence of true radial hypoplasia).

Evidence basis: Information is derived overwhelmingly from aggregated case series/registries (largest published cohorts ~40–150 patients; GeneReviews estimates ~200 total reported cases) rather than large-scale EHR data, reflecting the disease's rarity — this should be flagged as a HUMAN_CLINICAL evidence base of modest cohort size throughout curation, with wide confidence intervals on any reported frequency.

Sources: SALL1-Related Townes-Brocks Syndrome – GeneReviews, OMIM #107480, Orphanet, Townes-Brocks syndrome genotype-phenotype correlations, EJHG 2025

2. Etiology

Disease causal factor: Purely genetic/monogenic — heterozygous pathogenic (predominantly truncating) variants in SALL1. There is no known environmental, infectious, or toxic etiology; TBS1 is a primary developmental-genetic disorder.

Genetic risk factors: - Virtually all reported pathogenic variants are truncating (nonsense, frameshift, small indels) clustered in exon 2 (the second, and largest, coding exon) or occasionally intron 2, predicted to remove all C2H2 zinc-finger DNA-binding domains distal to the truncation point. - p.Arg276Ter (R276X), from a recurrent c.826C>T hotspot, is the most frequently reported single variant, found preferentially in sporadic rather than familial cases and associated with a more severe phenotype (94% classic triad; ~50% congenital heart disease, including the only reported SALL1-associated tetralogy of Fallot cases) (PMID:14627694, Botzenhart et al. 2007 hotspot-refinement study). - Genotype-phenotype trend: variants toward the 5′ end of the truncated protein and the canonical hotspot region tend to associate with more severe/complete phenotypes; whole-gene or large deletions removing only SALL1 tend to produce a milder phenotype than hotspot truncating point variants — evidence favoring a dominant-negative mechanism for truncating alleles rather than pure haploinsufficiency (see Mechanism section) (PMC9956891; PMC12583617/PMID:40348827). - ~50% of cases are de novo, with a strong parent-of-origin skew toward the paternally derived allele (~87.5%) per GeneReviews. - Somatic/gonadal mosaicism has been documented in at least 4 families, relevant to recurrence-risk counseling even when parents appear clinically unaffected. - A distinguishing genotype-phenotype note: p.Arg1054Ter causes a severe phenotype only in homozygosity; heterozygous carriers are reportedly unaffected — an exception to the general dominant/truncating rule and worth flagging explicitly if curated (do not generalize haploinsufficiency/dominant-negative claims across all truncating alleles without this caveat).

Environmental/lifestyle risk factors: None established. This is not a multifactorial or exposure-modulated disease in the current literature.

Protective factors: None described in humans. In the mouse model (see Mechanism/Model Organisms), the truncated Sall1 protein has been reported to confer protection from acute kidney injury (ischemia-reperfusion, aristolochic-acid nephrotoxicity) relative to wild-type — an intriguing but purely model-organism finding that should not be extrapolated to human protective factors (MODEL_ORGANISM evidence only; AJP-Renal 2015, doi 10.1152/ajprenal.00222.2015).

Gene-environment interactions: None reported; not applicable for this disorder.

Sources: Botzenhart 2007 hot spot refinement (PMID:17221874), High incidence of R276X (PMID:14627694), EJHG 2025 genotype-phenotype (PMID:40348827), CMA-identified deletion, milder phenotype (PMC9956891)

3. Phenotypes

Frequencies below are drawn from GeneReviews' synthesis of the published cohort literature (~200 reported cases); treat these as pooled case-series estimates, not population-representative rates, and always attribute per-source when curating individual evidence items.

Phenotype	Frequency	Onset	Suggested HPO term
Imperforate anus / anal stenosis	~70–84%	Congenital	HP:0002251 (Imperforate anus) / HP:0002032 (Atresia of the small intestine — not this; use HP:0002028? — prefer HP:0002251 Imperforate anus, and HP:0025286 Anal stenosis if graded)
Dysplastic/malformed ears (overfolded superior helix, "lop ear," preauricular tags)	~87%	Congenital	HP:0000411 (Protruding ear) / HP:0009909 (Overfolded helix) / HP:0000384 (Preauricular skin tag)
Sensorineural and/or conductive hearing loss	~62%	Congenital, may progress	HP:0000407 (Sensorineural hearing impairment), HP:0000405 (Conductive hearing impairment), HP:0000365 (Hearing impairment, unspecified type)
Thumb malformation: triphalangeal thumb, preaxial polydactyly, rarely thumb hypoplasia	~76–89%	Congenital	HP:0001199 (Triphalangeal thumb), HP:0001177 (Preaxial polydactyly), HP:0009601 (Thumb hypoplasia)
Renal structural/functional anomaly (hypoplasia/dysplasia, agenesis, multicystic/polycystic kidney, malrotation, ectopia, horseshoe kidney, VUR) — with or without progressive functional impairment to ESKD	~40% reported structural/functional; renal failure specifically 29.3–39.6% across series	Congenital structural; functional decline can present from infancy through adulthood	HP:0000121 (Nephropathy) / HP:0000107 (Renal cyst) / HP:0000104 (Renal agenesis) / HP:0012622 (Chronic kidney disease) / HP:0000083 (Renal insufficiency)
Foot malformations (flat feet, overlapping toes, clubfoot)	Common, exact % variable	Congenital	HP:0001883 (Preaxial foot polydactyly) / HP:0001762 (Talipes equinovarus)
Genitourinary anomalies (hypospadias, bifid uterus, vaginal aplasia, cryptorchidism, bifid scrotum)	~22%	Congenital	HP:0000047 (Hypospadias), HP:0000130 (Vaginal atresia/aplasia), HP:0000028 (Cryptorchidism)
Congenital heart disease (VSD, tetralogy of Fallot)	~15% overall (~50% in R276X carriers)	Congenital	HP:0001629 (Ventricular septal defect), HP:0001636 (Tetralogy of Fallot)
Developmental delay / learning difficulty	~15%	Childhood	HP:0001263 (Global developmental delay)
Hypothyroidism	Rare, reported in case series	Any age	HP:0000821 (Hypothyroidism)
Ocular anomalies (iris/chorioretinal coloboma, Duane anomaly)	Rare	Congenital	HP:0000612 (Iris coloboma), HP:0007803 (Chorioretinal coloboma), HP:0009921 (Duane anomaly)
Chiari I malformation	Rare	Any age (may be later-recognized)	HP:0007099 (Chiari type I malformation)
Growth deficiency (short stature; occasionally growth hormone deficiency)	Rare-occasional	Childhood	HP:0004322 (Short stature)
Umbilical hernia, dorsal corpus callosum hypoplasia (Botzenhart 2005 rare-feature list)	Rare	Congenital	HP:0001537 (Umbilical hernia), HP:0002079 (Hypoplasia of the corpus callosum)

Severity/progression pattern is a critical curation point. Hearing loss and renal function are explicitly noted in the literature as able to worsen at any age — several patients are diagnosed in adulthood, sometimes only after presenting with unexplained end-stage renal disease (ESRD) and retrospective recognition of the ear/thumb triad (PMID:33438842 "Adult diagnosis of Townes-Brocks syndrome with renal failure"; PMID:9072124 "Townes-Brocks syndrome presenting as end stage renal failure"; PMID:17910067 "Kidney failure in Townes-Brocks syndrome: an under-recognized phenomenon?"). This argues for lifelong audiologic and renal surveillance rather than a childhood-only screening model, and for coding onset/course qualifiers (progressive, variable) on the renal and auditory phenotype nodes rather than treating them as static congenital findings only.

Quality of life impact: Not separately quantified with validated instruments (EQ-5D/SF-36) in the literature reviewed; qualitative impact is driven mainly by (1) hearing loss affecting speech/language development if unaddressed, (2) surgical burden and long-term bowel/continence function after anorectal malformation repair, and (3) burden of chronic kidney disease/dialysis/transplantation in the subset that progresses to ESKD.

Sources: GeneReviews NBK1445, Kidney failure under-recognized (PMID:17910067), Adult diagnosis with renal failure (PMID:33438842), ESRF presentation (PMID:9072124)

4. Genetic/Molecular Information

Causal gene: SALL1 (Spalt-Like Transcription Factor 1), HGNC:10524, chromosome 16q12.1, OMIM 602218. Ortholog of Drosophila homeotic gene spalt (sal). Encodes a C2H2 double-zinc-finger transcriptional repressor with four zinc-finger clusters, localizing predominantly to pericentromeric heterochromatin/heterochromatic foci*.

Variant spectrum: - Nearly all pathogenic variants are truncating — nonsense, frameshift-causing small insertions/deletions — clustering within exon 2 (or intron 2 splice-affecting variants), predicted to eliminate all or most of the C-terminal zinc-finger domains. - Missense variants and variants outside this hotspot region are rare and, when reported, should be interpreted cautiously per ACMG/AMP criteria (PVS1 typically applies for the truncating hotspot class; missense variants require stronger orthogonal evidence). - Large whole-gene deletions (detected by chromosomal microarray/CNV analysis) also cause TBS1 but are associated with a milder phenotype than the recurrent truncating point variants — a genotype-phenotype dissociation directly supporting a dominant-negative (not simple loss-of-function/haploinsufficiency) mechanism for the truncating class (PMC9956891). - A technical caveat for molecular diagnosis: a highly homologous pseudogene, SALL1P1, can confound capture-based NGS panel interpretation of SALL1 variants (GeneReviews).

Functional consequence / mechanism classification: Best modeled in functional_impact_category as DOMINANT_NEGATIVE for the truncating hotspot class (not simple LOSS_OF_FUNCTION), based on converging human genotype-phenotype and mouse genetic evidence (see Mechanism section below) — though GeneReviews itself hedges as "loss of function and possible dominant-negative effect," so this should be curated as the leading but not fully settled model, with the haploinsufficiency-only alternative explicitly noted (design-decisions §3a-style lump/split discipline: don't quietly resolve an open mechanistic question).

Population/allele frequency: SALL1 loss-of-function variants are appropriately rare/absent as common polymorphisms in population databases (gnomAD) consistent with a highly penetrant dominant disease mechanism; no specific pooled gnomAD constraint metric was independently verified in this pass and should be confirmed against gnomAD directly before citation (pLI/LOEUF for SALL1 is a plausible high-constraint value but was not verified here — flag as unverified rather than asserting a specific number).

Modifier genes: None firmly established; phenotypic variability even within families carrying the identical variant (documented in multiple case reports) suggests stochastic/epigenetic or unidentified modifier effects, but no specific modifier locus has been validated.

Somatic vs. germline: TBS1 is exclusively a germline disorder; SALL1 truncating variants are not established somatic cancer drivers in the way some other developmental genes are, so COSMIC/somatic databases are not relevant here.

Chromosomal abnormalities: Reported causal mechanism also includes contiguous gene deletions/CNVs spanning SALL1 at 16q12.1 (detectable by CMA), distinct from the more common intragenic truncating point variants.

Epigenetics: SALL1's own protein product functions partly through recruitment of the NuRD (nucleosome remodeling and deacetylase) chromatin-remodeling complex to regulate nephron progenitor gene expression (Development 2017, "A Sall1-NuRD interaction regulates multipotent nephron progenitors and is required for loop of Henle formation") — this is a mechanistic/epigenetic-regulator role of the gene product itself, not a reported disease-associated DNA methylation signature in patients; no patient-derived EWAS/methylation study for TBS1 was identified in this search.

Suggested ontology bindings: gene hgnc:10524 (SALL1); GO molecular function GO:0003700 (DNA-binding transcription factor activity), GO:0001227 (DNA-binding transcription repressor activity, RNA polymerase II-specific).

Sources: OMIM *602218 SALL1, Netzer et al. 2001, SALL1 TRF1/PIN2 pericentromeric heterochromatin (PMID:11751684), Sall1-NuRD nephron progenitors (Development 2017)

5. Environmental Information

Not applicable. TBS1 is a monogenic disorder with no known environmental toxin, lifestyle, or infectious contributor to disease causation. (Contrast with the "protective in an induced-injury mouse model" finding above, which is a downstream physiological observation about the mutant protein, not an environmental etiologic factor.) No entry should be created in environmental: unless a genuinely disease-modifying exposure (e.g., a specific nephrotoxin accelerating renal decline in a SALL1 carrier) is identified in future literature; none was found here.

6. Mechanism / Pathophysiology

Ordered causal chain (numbered, with inference flagged)

A de novo or inherited heterozygous truncating variant in SALL1 (predominantly clustered in exon 2, most commonly the recurrent c.826C>T / p.Arg276Ter hotspot) removes the C-terminal zinc-finger DNA-binding/protein-interaction domains of the SALL1 repressor, while typically sparing translation and stable expression of an N-terminal truncated protein — demonstrated directly in patient-derived cells (PMID:18470945, Kiefer et al. 2008, Human Mutation).
This truncated protein retains a self-association/heterochromatin-targeting domain and, rather than being simply absent (haploinsufficiency), co-aggregates with the wild-type SALL1 protein product of the normal allele, mislocalizing it away from its normal pericentromeric heterochromatic foci — this is the biochemical basis proposed for a dominant-negative mechanism (built on SALL1's normal heterochromatin-targeting behavior described in Netzer et al. 2001, PMID:11751684; direct dominant-negative transcriptional consequence shown in Kiefer et al. 2008, PMID:18470945, where truncated SALL1 caused ectopic activation of downstream target genes rather than mere loss of repression).
Loss of correct SALL1-mediated transcriptional repression, at the wrong dose and/or at the wrong nuclear location, leads to ectopic/dysregulated expression of SALL1 target genes in the tissues where SALL1 is normally expressed during embryogenesis — this step is demonstrated in patient cell lines and knock-in mouse models but the full identity of relevant human target genes in each affected tissue remains incompletely characterized (an explicit knowledge gap).
Downstream, tissue-specific consequences result from disruption of three principal SALL1-dependent embryonic programs, each contributing a branch of the phenotype:
4a. Anorectal/cloacal development branch → disruption of normal hindgut/cloacal septation and anal canal formation → imperforate anus / anal stenosis (HP:0002251). Mechanistic detail in humans is incompletely resolved; supportive evidence is largely from mouse Sall1/Sall4 double-mutant studies showing cooperative roles in anorectal, cardiac, and CNS development (Development 2006, "murine homolog of SALL4... cooperates with Sall1 in anorectal, heart, brain and kidney development").
4b. Limb (thumb/first digit) development branch → SALL1 (with functional redundancy from SALL4) is expressed in the posterior limb bud and near the apical ectodermal ridge (AER), where it participates in patterning the anterior (preaxial) limb field → disruption leads to duplication (preaxial polydactyly, triphalangeal thumb) rather than the loss-of-structure pattern (radial hypoplasia) characteristic of the SALL4-related Okihiro/Duane-radial-ray spectrum — a key phenotypic distinguisher supported directly by a transgenic mouse expressing the truncated protein alone, which was sufficient to reproduce the limb phenotype (Kohlhase group, Hum Mol Genet 2003, "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes–Brocks syndrome birth defects," PMID not independently re-verified numerically here but DOI academic.oup.com/hmg/article/12/17/2221).
4c. Ear/hearing branch → disrupted SALL1-dependent patterning of the developing external and possibly inner ear structures → leads to dysplastic pinna morphology (overfolded helix, preauricular tags) and, independently or in parallel, sensorineural and/or conductive hearing impairment — the precise inner-ear cellular mechanism for the sensorineural component is not fully elucidated in the literature surveyed here (flag as a knowledge gap; candidate mechanism by analogy to other developmental hearing-loss genes would be a cochlear/otic-vesicle patterning defect, but this is inferred, not directly demonstrated for SALL1).
4d. Kidney (nephron progenitor) branch → SALL1 is required, together with NuRD-complex recruitment, to maintain the multipotent nephron progenitor pool, balancing progenitor self-renewal versus premature differentiation, and (independently) is required in the metanephric mesenchyme to attract ureteric bud outgrowth, plausibly via mesenchyme-derived GDNF signaling → disruption leads to a spectrum from mild renal hypoplasia/dysplasia/malrotation through multicystic dysplastic kidney to (in the mouse null) complete renal agenesis; this same progenitor-pool/nephron-number deficit is proposed to underlie later, progressive loss of renal function/CKD-to-ESKD in patients even when the kidney appears only mildly structurally abnormal at birth — this progression step (structural anomaly/reduced nephron endowment → oligonephronic hyperfiltration → progressive CKD → ESKD) is a plausible but partially inferred mechanistic bridge in humans, built on (i) the mouse developmental biology (Nishinakamura et al. 2001, PMID:11688560, Development; Kobayashi 2017 Sall1-NuRD paper) and (ii) the clinical observation that renal failure can present or progress independent of severe structural anomaly and at any age (PMID:17910067; a 2026 case report using serial kidney biopsies to document progressive glomerular pathology, "Serial Kidney Biopsies Reveal Progressive Pathology in Townes-Brocks Syndrome," Kidney Medicine).
Homozygous/biallelic loss of SALL1 (not the human disease genotype, but informative for mechanism) causes complete bilateral renal agenesis in mice, establishing that SALL1 dosage is on a severity gradient from mild heterozygous dysplasia (human TBS1) to complete agenesis (biallelic loss) — consistent with, though not proof of, a dosage-graded pathway in which the dominant-negative truncated allele behaves functionally "worse than" a simple null heterozygote for some tissues, explaining why truncating variants can be more severe than whole-gene deletions (point 4d converges with the genotype-phenotype data in Etiology).

Category detail

Molecular pathways: SALL1 acts as a transcriptional repressor recruiting the NuRD chromatin remodeling/deacetylase complex; interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin (PMID:11751684). No canonical signaling pathway (Wnt/MAPK/mTOR) has been established as the direct SALL1 mechanism in TBS1 itself, though SALL genes intersect with limb-patterning networks (Shh/Gremlin1/Tbx2 signaling context) via their role in AER-adjacent limb bud gene expression.
Cellular processes: Nephron progenitor self-renewal vs. differentiation balance (Sall1 in mouse metanephric mesenchyme); heterochromatin organization/gene silencing; apoptosis of metanephric mesenchyme in the SALL1-null state.
Protein dysfunction: Premature-truncation → stable but mislocalizing/aggregating repressor protein → dominant-negative sequestration of wild-type SALL1 (and possibly co-repressor complex components) away from correct heterochromatic targets.
Tissue damage mechanisms: In the kidney, the proposed chronic-injury mechanism is reduced functional nephron mass/oligonephronic state → compensatory hyperfiltration → progressive glomerulosclerosis (consistent with, though not proven identical to, the pattern documented by the serial-biopsy case report referenced above); this should be curated as INFERRED/model-supported rather than fully human-mechanism-proven.
Cell types involved (CL): metanephric mesenchymal cell (nephron progenitor), CL:0002520 (or CL:1000384 nephron progenitor cell) and ureteric bud epithelial cell (CL:1001430) for the kidney branch; limb bud mesenchymal cell for the digit branch; otic/auricular precursor cell for the ear branch (exact CL term for auricular cartilage precursor not verified — flag as needing dismech-terms lookup rather than asserting one from memory).
Molecular profiling / omics: No large-scale patient transcriptomic, proteomic, or single-cell dataset specific to TBS1 patient tissue was identified in this search; mouse Sall1-GFP knock-in and microarray studies have been used to define the kidney mesenchymal gene expression program downstream of Sall1 (PMID:15172686), which is the closest available "omics" resource and is model-organism, not patient, data.

Suggested GO biological process terms: GO:0072164 (mesonephric tubule development)/GO:0001656 (metanephros development), GO:0090190 (positive regulation of branching involved in ureteric bud morphogenesis) — negatively regulated in disease, GO:0072028 (nephron morphogenesis).

Sources: Kiefer 2008 ectopic gene expression (PMID:18470945), Netzer 2001 heterochromatin/TRF1-PIN2 (PMID:11751684), Nishinakamura 2001 Sall1 kidney agenesis (PMID:11688560), Sall1-NuRD nephron progenitors, Development 2017, Truncated Sall1 sufficient for limb phenotype, HMG 2003

7. Anatomical Structures Affected

Organ level (primary): - Anorectum/hindgut — imperforate anus, anal stenosis - External and middle/inner ear — pinna dysplasia; sensorineural and conductive hearing apparatus - Upper limb (thumb/first ray) and, less prominently, lower limb/foot - Kidney and urinary tract — dysplasia, hypoplasia, cystic disease, agenesis, vesicoureteral reflux - Genital tract (secondary/associated): hypospadias, bifid uterus, vaginal aplasia, cryptorchidism

Secondary/complication-level organ involvement: - Heart — septal defects, tetralogy of Fallot (notably enriched in R276X carriers) - Thyroid — occasional hypothyroidism - Eye — iris/chorioretinal coloboma (rare) - CNS — Chiari I malformation, corpus callosum hypoplasia (rare); developmental delay/learning difficulty in a minority - Musculoskeletal (foot) — clubfoot, overlapping toes, flat feet

Body systems involved: digestive (anorectal), auditory/otic, musculoskeletal (limb), renal/urinary, reproductive/genital, cardiovascular, endocrine (thyroid), ophthalmologic, neurologic (minor subset).

Tissue/cell level: - Metanephric mesenchyme and nephron progenitor cells (kidney) - Ureteric bud epithelium (kidney collecting system) - Cochlear/vestibular and middle-ear ossicular structures (hearing) - Auricular cartilage and skin (ear dysplasia, preauricular tags) - Limb bud mesenchyme, apical ectodermal ridge-adjacent tissue (digit patterning) - Cloacal membrane/hindgut endoderm and surrounding mesenchyme (anorectal)

Subcellular level: SALL1 protein localizes to pericentromeric heterochromatin within the nucleus (GO:0005720 pericentric heterochromatin) — this is the key subcellular compartment implicated mechanistically, since the truncated protein's mislocalization/aggregation there is central to the proposed dominant-negative model.

Localization/laterality: Renal, ear, limb, and cardiac anomalies can each be unilateral, bilateral, or asymmetric between sides in an individual patient (e.g., unilateral renal agenesis with contralateral normal kidney is reported); imperforate anus is midline by definition. No consistent, obligate lateralization pattern is described.

Suggested UBERON terms: UBERON:0000059 (large intestine)/UBERON:0004907 (anal canal), UBERON:0001690 (ear), UBERON:0002113 (kidney), UBERON:0002544 (thumb).

8. Temporal Development

Onset: Congenital for the core structural triad (anorectal, ear, thumb anomalies) — present and typically recognized at birth or in early infancy given the visible nature of imperforate anus and ear dysplasia. High-resolution prenatal ultrasound can detect phenotypic features (limb anomalies, some renal anomalies) from approximately 16 weeks' gestation onward once a familial pathogenic variant is known (GeneReviews).

Onset pattern: Structural anomalies are present at birth (congenital, not acquired); functional manifestations — most importantly hearing loss and renal function decline — can have delayed or progressive onset, occurring at essentially any age from infancy through adulthood. This is explicitly emphasized in the literature ("renal failure and deafness can occur at any age, making follow-up essential") and is supported by multiple adult-onset diagnostic case reports where TBS1 was first recognized because of unexplained ESRD in adulthood (PMID:33438842, PMID:9072124).

Progression: - Anorectal, limb, and ear structural anomalies are static/non-progressive once formed (surgical correction addresses function, not an evolving structural process). - Renal disease course ranges from stable mild structural anomaly with normal lifelong function, to slowly progressive chronic kidney disease, to end-stage kidney disease requiring dialysis/transplantation — reported in a substantial minority (~29–40% across series). A 2026 case report using serial biopsies specifically documents progressive glomerular pathology over time in an affected individual, directly supporting a genuinely progressive (not merely static-congenital) renal phenotype in at least some patients. - Hearing loss can range from mild and stable to severe and may itself be progressive in some patients (GeneReviews; exact proportion progressive vs. stable not separately quantified in the sources reviewed here).

Disease course pattern: Best characterized as a stable congenital malformation complex with a superimposed, variably progressive organ-functional component (renal, auditory) rather than either a purely static syndrome or a uniformly progressive disease — this composite pattern should be reflected in progression: entries that separate structural (stable) from functional (progressive/variable) phenotypes rather than assigning one course descriptor to the whole entry.

Critical periods: The main clinically actionable "critical period" is the immediate neonatal period, when imperforate anus requires urgent surgical correction, and early childhood, when timely identification and management of hearing loss is critical to avoid secondary speech/language impairment.

9. Inheritance and Population

Epidemiology: - Estimated frequency ~1 in 250,000 live births (commonly cited figure, e.g., NORD/Orphanet-derived); a more recent estimate from monogenic-kidney-disease-panel testing data reported the SALL1 pathogenic variant carrier prevalence as 1 in ~238,000–342,000 in the general population depending on the specific study/denominator used, and notably 1 in 1,592 among individuals ascertained for monogenic kidney disease testing, and 1 in 2,952 among hearing-loss cohorts — reflecting substantial ascertainment bias toward these two organ-specific testing pathways (GeneReviews synthesis of multiple cohort-testing studies). - Only ~200 patients are reported in the medical literature to date per GeneReviews, underscoring the rarity and the wide uncertainty around any single prevalence figure.

Inheritance pattern: Autosomal dominant.

Penetrance: Reported as ~100% once the full mild-to-severe phenotypic spectrum is considered (i.e., essentially no asymptomatic obligate carriers when comprehensively examined), though individual features (e.g., renal failure, hearing loss) are incompletely penetrant/variable in timing.

Expressivity: Highly variable, even within the same family and among carriers of the identical pathogenic variant — ranging from isolated dysplastic-ear/hearing-loss presentations (mimicking branchio-oto-renal syndrome) to the full multi-organ triad-plus phenotype with ESKD and congenital heart disease.

Genetic anticipation: Not described/not applicable — TBS1 is not a repeat-expansion disorder.

Germline mosaicism: Documented in at least 4 reported instances, relevant to recurrence-risk counseling for apparently unaffected parents of an affected child.

Founder effects: No specific population founder variant is established; the R276X hotspot arises recurrently (mutational hotspot at a CpG-type site) rather than reflecting a single ancestral founder haplotype, and is seen preferentially in sporadic cases (arguing against a shared-ancestry founder explanation and for recurrent independent mutation at this site).

Consanguinity: Not a relevant risk factor for this autosomal dominant disorder (consanguinity is relevant to recessive disease; TBS1 risk is driven by de novo mutation rate or transmission from an affected/mosaic dominant carrier, not parental relatedness).

Carrier frequency: Not meaningfully applicable in the traditional AR-disease sense; the relevant population parameter is de novo mutation rate plus a small pool of affected/transmitting individuals given reduced reproductive fitness in more severely affected cases.

Population demographics: - No specific ethnic or geographic enrichment is established in the literature surveyed; cases have been reported from multiple populations (e.g., Chinese, Brazilian, European cohorts appear repeatedly in the case-report literature retrieved here), consistent with a pan-ethnic disorder driven by recurrent de novo mutation rather than population-specific founder effects. - Sex ratio: No sex predilection is reported; autosomal dominant inheritance is consistent with equal male:female occurrence. - Age distribution: Bimodal ascertainment pattern in practice — most patients are diagnosed in infancy/early childhood because of the visible anorectal/ear/limb triad, but a clinically important subset is diagnosed only in adulthood, typically via unexplained renal failure or hearing-loss/kidney gene panel testing.

Sources: GeneReviews NBK1445, Kidney Gene Panel Testing reveals TBS (ScienceDirect)

10. Diagnostics

Clinical diagnostic criteria: No single formal consensus scoring system (akin to DSM/ICD criteria) is standardized in the literature; diagnosis is clinically suspected from the triad (imperforate anus/anal stenosis + dysplastic ears ± hearing loss + thumb malformation) and confirmed molecularly. GeneReviews-cited series report the individual triad components at roughly 70–89% each (see Phenotypes table), meaning not all three need be present for clinical suspicion, particularly given the mild end of the spectrum (isolated ear/hearing phenotype).

Genetic testing (primary diagnostic modality): - First-tier gene-targeted testing: SALL1 sequence analysis — detects >90% of pathogenic variants — followed by deletion/duplication (CNV) analysis (chromosomal microarray or MLPA/targeted CNV assay) if sequencing is negative but clinical suspicion remains high, given the described whole-gene-deletion allelic class. - Multigene panel: SALL1 plus SALL4 and other differential-diagnosis genes (e.g., EYA1/SIX1, TBX5), useful when the phenotype is atypical or overlaps a differential category. - Comprehensive genomic testing: Exome/genome sequencing appropriate for atypical presentations without a clear triad. - Technical pitfall: the SALL1P1 pseudogene can interfere with capture-based NGS panel variant calling at the SALL1 locus — worth flagging in any notes: field discussing testing methodology. - Chromosomal microarray (CMA): Specifically useful for detecting the whole-gene-deletion allelic class associated with the milder phenotype.

Imaging/functional/laboratory workup (used for phenotype characterization and management rather than primary diagnosis): - Renal ultrasound at diagnosis and longitudinally (structural anomaly detection: hypoplasia, cysts, agenesis, malrotation, horseshoe kidney, VUR). - Renal function laboratory monitoring (serum creatinine/eGFR) — explicitly recommended annually in all individuals regardless of baseline normalcy, given the risk of functional decline independent of structural anomaly. - Audiology (behavioral/objective hearing testing) at diagnosis and annually thereafter given the risk of progressive loss. - Echocardiogram at diagnosis, particularly emphasized for R276X carriers given the elevated congenital-heart-disease rate. - Skeletal/orthopedic examination of hands and feet. - Ophthalmologic examination as clinically indicated. - Thyroid function testing given occasional hypothyroidism. - Developmental/behavioral assessment, annually.

Prenatal diagnosis: Once a familial SALL1 pathogenic variant is identified, prenatal molecular testing (chorionic villus sampling/amniocentesis) or preimplantation genetic testing is possible; high-resolution ultrasound can also detect structural features (limb, some renal) from mid-second trimester (~16 weeks) onward. Notably, GeneReviews states that except for the R276X genotype (which reliably predicts a severe phenotype), genotype cannot reliably predict the severity of specific manifestations for prenatal counseling purposes — an important caveat against over-promising prognostic precision from prenatal genetic results alone.

Differential diagnosis (critical for correct curation — do not conflate these distinct entities): - SALL4-related Duane-radial ray syndrome (Okihiro syndrome) — distinguished by radial/forearm involvement (true radial hypoplasia, absent in TBS1) and Duane anomaly; test SALL4 if radial or Duane features present. - Branchiootorenal (BOR) spectrum disorder (EYA1/SIX1/SIX5) — branchial fistulae/cysts characteristic; lacks thumb malformations. Particularly relevant because mild TBS1 (isolated ear/hearing/renal phenotype without triad) can closely mimic BOR. - Holt-Oram syndrome (TBX5) — carpal bone anomalies and cardiac septal defects but no typical ear dysplasia or anorectal anomaly. - VACTERL association — important differential especially for sporadic/simplex presentations; severe vertebral anomalies and tracheoesophageal fistula are not features of SALL1-related TBS1 and their presence argues against this diagnosis. - Townes-Brocks syndrome 2 (DACT1-related) — lacks thumb anomalies; a genetically distinct entity that must be kept separate in curation per the dismech lump/split discipline. - Goldenhar syndrome/hemifacial microsomia spectrum — ear anomaly overlap; a specific paper (Genetics in Medicine, "Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia") documents diagnostic overlap and the SALL1 hotspot's relevance to this differential.

Suggested NCIT term for genetic testing modality: NCIT:C101294 (approx. "Genetic Testing") — verify exact CURIE via OAK before binding.

Sources: GeneReviews NBK1445, TBS vs. hemifacial microsomia (Genetics in Medicine), SALL4-Related Disorders GeneReviews

11. Outcome/Prognosis

Survival/mortality: No population-level survival statistics (5-/10-year survival curves, SEER-style data) exist for this ultra-rare disorder. Mortality risk, where it exists, is driven primarily by the minority of patients who progress to end-stage kidney disease and its associated morbidity, and — much less commonly — by significant congenital heart disease (tetralogy of Fallot) in the R276X subgroup. With modern surgical and renal-replacement management, overall life expectancy for most TBS1 patients (those without severe renal/cardiac involvement) is not reported as significantly reduced.

Morbidity/functional outcomes: - Renal: the dominant driver of long-term morbidity in the more severely affected subset; 29–40% of reported patients develop renal failure, some progressing to dialysis-dependent ESKD and requiring kidney transplantation. - Auditory: untreated/undiagnosed progressive hearing loss carries risk of speech-language developmental impact if not identified and managed (hearing aids, early intervention) promptly. - Bowel/continence: long-term function after anorectal malformation repair varies with the severity of the original anomaly and surgical outcome, as in anorectal malformations generally; TBS1-specific continence outcome data were not separately identified in this search. - Musculoskeletal: hand function after thumb anomaly correction is generally favorable with appropriate surgical management. - Developmental: ~15% experience developmental delay/learning difficulty, a minority but a real burden for those affected.

Complications: Recurrent/progressive CKD-to-ESKD; hypothyroidism (if undiagnosed, systemic metabolic consequences); congenital heart disease-related complications in the R276X subgroup; secondary complications of chronic hearing loss if unmanaged.

Prognostic factors: - Genotype is the single most informative prognostic factor identified: the R276X hotspot variant predicts a high likelihood of the full classic triad (94%) and a markedly elevated risk of congenital heart disease (~50%), useful for anticipatory cardiac screening. - Whole-gene deletion genotype predicts a comparatively milder overall phenotype than hotspot truncating variants. - Beyond these two genotype classes, GeneReviews explicitly notes that specific manifestation severity cannot be reliably predicted from genotype for prenatal/genetic counseling purposes — an important, honestly-stated limitation rather than an unqualified genotype-phenotype prediction claim. - Presence of any renal structural anomaly at diagnosis, and baseline renal function, are the most direct clinical prognostic indicators for future kidney trajectory, which is why annual renal function monitoring (regardless of baseline normalcy) is specifically recommended — implying that even a "normal-appearing" baseline does not exclude later decline.

Sources: GeneReviews NBK1445, Delayed diagnosis with kidney failure (PMC12779858), Serial Kidney Biopsies, Progressive Pathology in TBS, Kidney Medicine

12. Treatment

There is no disease-modifying or gene-targeted therapy for TBS1; management is entirely surgical, supportive, and surveillance-based, directed at each organ-system manifestation.

Surgical/interventional: - Anorectal malformation repair — urgent/early surgical correction of imperforate anus in the neonatal period (staged anoplasty/colostomy approach as per standard anorectal malformation surgical protocols). Suggested NCIT term: NCIT:C15329 (Surgical Procedure) as the general treatment_term, with preferred_term specifying anorectoplasty. - Thumb/hand surgical correction for severe polydactyly or triphalangeal thumb impairing function, per standard hand-surgery approach. NCIT:C16186 (Orthopedic Surgical Procedure). - Cardiac surgery for structural congenital heart disease (VSD closure, tetralogy of Fallot repair) as clinically indicated, particularly relevant to screen for/anticipate in R276X carriers. NCIT:C15329. - Kidney transplantation for individuals progressing to ESKD. NCIT:C15289 (Organ Transplantation). - Cochlear implantation or other otologic surgical procedures may be relevant for select severe/conductive hearing-loss cases (general principle for severe congenital hearing loss; TBS1-specific cochlear implant outcome data were not separately identified in this search — flag as inferred from general otologic practice, not TBS1-specific evidence, if curated).

Supportive/medical: - Constipation management — stool softeners, laxatives, osmotic agents — a recurring post-anorectoplasty and general GI management need, per GeneReviews management table. NCIT:C15747 (Supportive Care) as general category; therapeutic_agent for specific laxative classes as needed. - Hearing aids and early audiologic intervention for identified hearing loss. No specific NCIT device term was independently verified for hearing-aid fitting; per dismech convention, bind the clinical action (e.g., NCIT:C15747 Supportive Care, or an appropriate rehabilitation term) and carry device specificity in preferred_term, verifying the exact CURIE via OAK before binding. - Renal replacement therapy — dialysis (hemodialysis/peritoneal) as a bridge to or alternative for kidney transplantation in ESKD. - Growth hormone therapy for the subset with documented growth hormone deficiency, per GeneReviews management recommendations. NCIT:C15986 (Pharmacotherapy) + therapeutic_agent (recombinant human growth hormone, somatropin — CHEBI/NCIT CURIE to be verified before binding). - Levothyroxine replacement for documented hypothyroidism (inferred standard-of-care management for a reported associated finding; not separately verified as TBS1-specific literature in this pass). - Rehabilitative therapy (physical/occupational/speech therapy) as clinically indicated for musculoskeletal or hearing-related functional impact. NCIT:C15302 (Physical Therapy) / NCIT:C159273 (Speech Therapy).

Medications to avoid: GeneReviews specifically flags avoidance of medications with nephrotoxic or ototoxic potential in TBS1 patients, given the baseline vulnerability of both organ systems — an important, disease-specific pharmacologic caution worth capturing explicitly (e.g., in notes: on relevant treatment or pathophysiology nodes) rather than only as a generic statement.

Experimental/investigational therapies: No SALL1-targeted molecular therapy (gene therapy, ASO, small molecule correcting the dominant-negative mechanism) has reached clinical development based on this search; no relevant ClinicalTrials.gov-registered interventional trial specific to TBS1 was identified. This is consistent with the disease's rarity and the current absence of a mechanism-specific pharmacologic target beyond standard organ-supportive care.

Treatment strategy: Best modeled as a lifelong, multidisciplinary surveillance-and-management algorithm (genetics, urology/nephrology, otolaryngology/audiology, cardiology, orthopedics/hand surgery, colorectal surgery, endocrinology, ophthalmology, developmental pediatrics) rather than a single linear treatment pathway, reflecting the multi-organ and variably progressive nature of the disease.

Sources: GeneReviews NBK1445 (management/surveillance table), NORD Townes-Brocks Syndrome

13. Prevention

Primary prevention: Not applicable in the traditional sense (no environmental/behavioral risk-factor modification exists for this monogenic, largely de novo disorder). The relevant "primary prevention" tool is genetic counseling and reproductive options for known carrier families (prenatal diagnosis, preimplantation genetic testing) rather than population-level risk-factor reduction.

Secondary prevention (early detection): - Newborn/early recognition of the visible triad (imperforate anus, ear dysplasia, thumb anomaly) is itself the practical "screening" mechanism that triggers confirmatory genetic testing and the subsequent surveillance cascade (renal ultrasound, audiology, echocardiogram) — early recognition is explicitly emphasized in the literature as key to preventing downstream morbidity (e.g., catching progressive hearing loss or renal decline before it causes irreversible harm). - Cascade/family screening: once a proband's SALL1 variant is known, testing at-risk relatives (including apparently unaffected parents, given variable expressivity) is recommended to identify mildly affected family members who might otherwise be missed and to inform recurrence risk.

Genetic counseling: Central to prevention/family planning in TBS1 — explaining the ~50% transmission risk per pregnancy for an affected parent, the possibility of germline mosaicism (and therefore non-negligible recurrence risk even with two apparently unaffected parents), the general inability to predict specific manifestation severity from genotype (except the R276X-severe association), and the availability of prenatal or preimplantation genetic testing once a familial variant is identified.

Tertiary prevention (preventing complications in affected individuals): This is where most of the disorder's "prevention" activity actually concentrates, per the GeneReviews surveillance table — annual renal function monitoring to catch and manage CKD progression before ESKD, annual audiology to catch progressive hearing loss early, avoidance of nephrotoxic/ototoxic medications, and routine cardiac, developmental, growth/thyroid, and ophthalmologic surveillance to catch and manage associated complications proactively rather than reactively.

Screening programs: No population-based newborn screening test exists (or would be expected, given the disorder's visible congenital presentation and extreme rarity); screening in practice is clinical (recognition-triggered) rather than a laboratory-based population screen.

Public health/environmental interventions: Not applicable — no environmental determinant to intervene upon.

14. Other Species / Natural Disease

Taxonomy: No naturally occurring TBS1-equivalent disease has been described in a non-human species in the literature surveyed here (i.e., this does not appear in OMIA as a veterinary/naturally occurring disease entity based on this search). TBS1 modeling in other species is exclusively via engineered/induced genetic models (see Model Organisms, below), not naturally occurring disease.

Orthologous gene: Mouse Sall1 (MGI ortholog of human SALL1) is the principal comparative-genetics resource; Sall1 and its paralog Sall4 show partial functional redundancy in several developmental contexts (hindlimb initiation, anorectal/cardiac/renal/CNS development), which is directly informative for understanding the human TBS1 (SALL1) vs. Okihiro/Duane-radial-ray syndrome (SALL4) phenotypic contrast — SALL4 human disease is predominantly a haploinsufficiency/radial-ray-loss phenotype whereas SALL1 human disease (TBS1) is predominantly a dominant-negative/digit-duplication phenotype, and comparative mouse genetics is the primary evidentiary bridge for this distinction (PNAS 2015 Sall4-Gli3 limb paper; Genetics 2024 "Sall genes regulate hindlimb initiation in mouse embryos," PMC11075541).

Comparative biology/evolutionary conservation: The requirement for a Sall1 ortholog in kidney (ureteric bud/nephron progenitor) development is explicitly described as "conserved over species" in comparative developmental biology literature (ScienceDirect, "Kidney development conserved over species: essential roles of Sall1"), spanning mouse and Xenopus pronephros induction systems, supporting cross-species conservation of the core SALL1 kidney-developmental mechanism even though disease itself is not naturally observed outside humans.

Zoonotic potential/transmission: Not applicable — TBS1 is a non-transmissible, purely genetic developmental disorder.

15. Model Organisms

Mouse (primary and best-characterized model):

Conventional Sall1-null (knockout) mice (Nishinakamura et al. 2001, Development 128:3105–3115, PMID:11688560): homozygous null mice die perinatally with kidney agenesis or severe dysgenesis due to failure of ureteric bud invasion/outgrowth into the metanephric mesenchyme, with mesenchymal apoptosis and failed tubule formation. This establishes SALL1's essential, dosage-graded role in early nephrogenesis and is the mechanistic anchor for the human renal phenotype, though it models biallelic loss, which is more severe than (and mechanistically distinct in degree from) the human heterozygous disease state.
Sall1 knock-in mouse expressing a truncated protein (Sall1ΔZn2-10 and related alleles) (Hum Mol Genet 2003, "Expression of a truncated Sall1 transcriptional repressor is responsible for Townes–Brocks syndrome birth defects"): this is the most disease-relevant model, as heterozygous knock-in mice recapitulate key human TBS features — high-frequency sensorineural hearing loss, renal cystic hypoplasia, and wrist/limb bone abnormalities — directly supporting the dominant-negative mechanism, since expressing the truncated protein alone (not simple SALL1 loss) is sufficient to cause the TBS-like phenotype. Homozygous truncated-protein mice show a more severe phenotype than Sall1-null homozygotes (complete renal agenesis, exencephaly, limb and anal deformities) — direct genetic evidence that the truncated protein is not behaving as a simple null allele.
Sall1TBS mouse model in induced acute kidney injury (AJP-Renal 2015, doi:10.1152/ajprenal.00222.2015): the same truncated-protein heterozygous model shows relative protection from ischemia-reperfusion injury and aristolochic-acid-induced nephrotoxicity compared to wild-type — an unexpected, model-organism-only finding whose translational relevance to human TBS1 kidney-injury susceptibility is undetermined and should be curated as a HUMAN_MODEL_MISMATCH-flavored open question rather than assumed to apply to patients.
Sall1-GFP knock-in mice (PMID:15172686) — used to isolate and transcriptionally profile the Sall1-expressing kidney mesenchymal cell population, informing the "molecular profiling" resource base for kidney-branch mechanism (see Section 6).
Sall1 in renal stromal progenitors (Scientific Reports, PMC4625151) — demonstrates a non-cell-autonomous role: Sall1 in the renal stromal progenitor compartment restrains excessive nephron progenitor expansion, adding nuance that SALL1's kidney role is not confined to the nephron progenitor/ureteric bud compartments alone.
Sall1-NuRD complex interaction and loop-of-Henle formation (Development 2017) — mechanistic dissection showing Sall1 acts as both an activator and a repressor via distinct interactions (including NuRD) to maintain nephron progenitors and enable normal nephron segmentation (loop of Henle formation specifically).
Sall1 role in cortical neurogenesis (PMC3339829, "Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome") — a mouse-model-derived candidate mechanism for the CNS-related findings (developmental delay, Chiari I malformation) occasionally reported in TBS1 patients; this extends the model's relevance beyond the classic triad+kidney axis but remains model-organism inferential evidence for the human CNS phenotype.
Sall1/Sall4 double-mutant mice (Development 2006) — demonstrate genetic cooperation between the two paralogs in anorectal, cardiac, brain, and kidney development, directly relevant to understanding both the TBS1 (SALL1) anorectal/cardiac phenotype and its mechanistic overlap with/distinction from SALL4-related disease.
Sall genes and hindlimb initiation (Genetics 2024, PMC11075541) — T-Cre-mediated Sall1/Sall4 conditional double knockouts fail to initiate hindlimbs at all (loss of Isl1/Pitx1/Tbx4 expression), establishing redundant essential function in limb-field specification broadly, with Sall1 alone (in the heterozygous truncated-protein model above) instead producing the milder, disease-relevant digit-duplication phenotype.

Phenotype recapitulation and limitations: The heterozygous truncated-protein knock-in mouse is judged the most faithful available model for the core TBS1 features (hearing loss, renal cystic hypoplasia, limb/wrist abnormality), directly supporting the human dominant-negative mechanistic hypothesis. Its principal limitations as a human-disease model include: (1) it does not reproduce every human-reported feature (e.g., anorectal/imperforate-anus phenotype recapitulation specifically in the heterozygous model was not confirmed as robust in the sources reviewed here — the anorectal phenotype is better documented in the Sall1/Sall4 double-mutant and homozygous truncated-protein contexts, which are not the direct heterozygous human-genotype equivalent); (2) the unexpected AKI-protective phenotype has no established human correlate and its translational meaning is unresolved; (3) as with any mouse model, species differences in nephron endowment, ear anatomy, and digit number/patterning limit one-to-one extrapolation of severity or timing.

Other model systems: No Drosophila, zebrafish, C. elegans, yeast, or human iPSC/organoid model specific to SALL1/TBS1 disease modeling was identified in this search (Drosophila spalt is the evolutionary ortholog underlying the gene family's discovery and naming, but was not found here as a disease-modeling platform for TBS1 specifically; Xenopus pronephros work is developmental-biology mechanism research rather than a TBS1 disease model per se). This is a plausible research gap worth flagging rather than asserting resources that were not found.

Resources: MGI (Mouse Genome Informatics) is the relevant repository for the Sall1 knockout and knock-in alleles described above; specific IMPC/KOMP allele identifiers were not independently retrieved in this pass and should be looked up directly in MGI before citing a specific allele ID.

Sources: Nishinakamura 2001 (PMID:11688560), Truncated Sall1 knock-in, HMG 2003, Sall1TBS AKI protection, AJP-Renal 2015, Sall1-NuRD, Development 2017, Sall1 cortical neurogenesis, PMC3339829, Sall genes hindlimb initiation, Genetics 2024, Sall1/Sall4 cooperation, Development 2006

Summary of Notable Curation Cautions for This Entry

Mechanism is genuinely unsettled between dominant-negative and haploinsufficiency — GeneReviews itself hedges ("loss of function and possible dominant-negative effect"). Curate functional_impact_category reflecting this as the best-supported-but-not-fully-resolved model, and surface (don't silently pick) the competing haploinsufficiency framing, per the dismech evidence-policy discipline on open mechanistic questions.
Renal and auditory phenotypes are progressive/variable-onset, not purely congenital-static — model onset/clinical_course qualifiers accordingly and do not code them as fixed congenital-only findings.
Keep TBS1 (SALL1) rigorously separate from TBS2 (DACT1) and from the SALL4-related Okihiro/Duane-radial-ray spectrum — these are genetically distinct entries with an important differentiating clinical feature (radial hypoplasia present in SALL4-related disease, absent in TBS1).
All prevalence figures are pooled small-case-series/panel-ascertainment estimates, not population-registry data — cite with appropriate caveats and avoid over-precise point estimates.
The mouse AKI-protection finding is model-organism-only and should not be represented as a human protective factor without explicit evidence_source: MODEL_ORGANISM and directness caveats.
Several specific PMIDs above (e.g., Kohlhase 1998 original Nat Genet report, Kiefer 2008 HMG paper's exact identifier beyond the confirmed PMID:18470945, and the HMG 2003 truncated-protein knock-in paper) should have their exact PMIDs independently re-verified via PubMed/just fetch-reference before being written into KB evidence items, per the dismech rule that a deep-research or web-search-derived citation is a lead, not a checked binding, until fetched and quote-verified through the repository's own reference pipeline.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	19
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	59
Resolved	57
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	24
Terms named correctly	19
Terms named as a different term	4
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0002251 (3 mentions) - the report calls it "imperforate anus / anal stenosis"; HP calls it Aganglionic megacolon
UBERON:0004907 (1 mention) - the report calls it "anal canal"; UBERON calls it lower digestive tract
UBERON:0002544 (1 mention) - the report calls it "thumb"; UBERON calls it digit
NCIT:C101294 (1 mention) - the report calls it "approx. "Genetic Testing"; NCIT calls it Whole Genome Sequencing

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0005720 (GO_0005720) (1 mention) - replaced by GO:0000792

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

NCIT:C159273 (1 mention) - the report calls it "Speech Therapy"; NCIT calls it Speech Language Therapy

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Townes-Brocks Syndrome 1 (TBS1) — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (numbered, with inference flagged)

Category detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Notable Curation Cautions for This Entry

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look