Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome
Open accessAbstract
SALL1 heterozygous pathogenic variants cause Townes–Brocks syndrome (TBS), a condition with variable clinical presentation. The main features are a stenotic or imperforate anus, dysplastic ears, and thumb malformations, and other common concerns are hearing impairments, foot malformations, and renal and heart defects. Most of the pathogenic SALL1 variants are nonsense and frameshift, likely escaping nonsense-mediated mRNA decay and causing disease via a dominant-negative mechanism. Haploinsufficiency may result in mild phenotypes, but only four families with distinct SALL1 deletions have been reported to date, with a few more being of larger size and also affecting neighboring genes. 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. 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. Chromosomal microarray analysis is still a valuable tool in the identification of atypical/mild TBS cases, which are likely underestimated.
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The molecular explanation underlying phenotypic evidence in animal models and phenotype-genotype correlations in TBS patients remained unclear to date.
“However to date, the molecular explanation underlying phenotypic evidence in animal models 25,29 and phenotypegenotype correlations in TBS patients 47,60,32 remained unclear.”
From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [32]
The Discussion says genotype–phenotype correlations in TBS patients have been debated and that more functional characterization is needed. But the paper also offers a molecular explanation—dominant-negative SALL1 variants for typical TBS and haploinsufficiency for milder phenotypes—so it does not support an unqualified statement that the explanation remained unclear. The animal-model evidence is attached to other citations in the citing sentence. (LLM, conf=0.82)
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“The utility of chromosomal microarray analysis (CMA) for the detection of copy number variants (CNVs) in patients with neurodevelopmental disorders and/or congenital malformation is widely acknowledged, and CMA (CGH and SNP array) has been recommended for the first-tier analysis for these indications since 2010 [1,2].”
BackgroundDECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources
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Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome
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“It is caused by mutations in SALL1 [8], which encodes a zinc finger transcription factor exclusively found in the nucleus and linked to chromatin-mediated repression [9].”
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“Interestingly, the same 3414_3415delAT mutation in SALL1 had also been described in a 17-year-old patient with bilateral renal hypodysplasia without any extrarenal manifestations [27].”
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“[11] 103/1 AT + + + + + + − 119/1 + + + + + − − NR 149/1 + + + − + + + NR 182/1 + + + + − − − + 186/1 + + + + + + − − 188/1 + + − − − − + − 205/1 AT + + + + NR + − 224/1 VPA + + + + + − − 224/2 + + + + − + − NR [22] AT + + + + NR − NR [23] + + + + + − + + [24] B934 NR + + NR + + NR NR [25] + + + NR + + + NR TOT 20 13/…”
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“[19] 3-1 + + + + + − − + 4-1 + + + + + − + − 5-1 − + + + + + + −”
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“Although more mutations should be functionally characterized in order to confirm these findings, a growing degree of severity can be hypothesized such as: (1) the complete absence of SALL1 is likely to be embryonic lethal, (2) a small amount of SALL1 function (with the homozygous p.R1054* mutation being the only examp…”
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“CMA can sometime identify deletions which affect one single gene, helping to figure out whether haploinsufficiency truly drives pathological phenotypes [3,4].”
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“Overall, the clinical presentation of TBS is highly variable [6,7].”
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“Overall, the clinical presentation of TBS is highly variable [6,7].”
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“[15] 1 1 VPA + + + + NR NR − 2 + + + − NR − − − 3 1 + + + + + − + −”
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“Arg276Ter, showing that this variant escapes nonsense-mediated decay (NMD) and supporting the hypothesis that expression of a truncated protein is critical in the pathogenesis of TBS [14].”
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“[20] TB6 + + + − + + − NR TB7 + + + − + − + NR TB8 + + + + + − + NR [21] 2 AT + + + NR + + NR”
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“[11] 103/1 AT + + + + + + − 119/1 + + + + + − − NR 149/1 + + + − + + + NR 182/1 + + + + − − − + 186/1 + + + + + + − − 188/1 + + − − − − + − 205/1 AT + + + + NR + − 224/1 VPA + + + + + − − 224/2 + + + + − + − NR [22] AT + + + + NR − NR [23] + + + + + − + + [24] B934 NR + + NR + + NR NR [25] + + + NR + + + NR TOT 20 13/…”
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“[11] 103/1 AT + + + + + + − 119/1 + + + + + − − NR 149/1 + + + − + + + NR 182/1 + + + + − − − + 186/1 + + + + + + − − 188/1 + + − − − − + − 205/1 AT + + + + NR + − 224/1 VPA + + + + + − − 224/2 + + + + − + − NR [22] AT + + + + NR − NR [23] + + + + + − + + [24] B934 NR + + NR + + NR NR [25] + + + NR + + + NR TOT 20 13/…”
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Flagged first, then by citations
2 of the 30 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
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Cited by
Sorted by citations
Landscape of Constitutional SOX4 Variation in Human Disorders
Grippa, M., & Graziano, C. (2024) · Genes · doi:10.3390/genes15020158 · Cited by 8
“As exemplified by SALL1 mutations in Townes–Brockes syndrome, haploinsufficiency can exert a milder effect than recurrent truncating variants escaping NMD, which act through a dominant-negative mechanism [43].”
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A novel SALL1 C757T mutation in a Chinese family causes a rare disease --Townes-Brocks syndrome
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BackgroundTetramerisation governs SALL transcription factor function in development and disease
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- Authors
- Innoceta, A. M., Olivucci, G., Parmeggiani, G., Scarano, E., Pragliola, A., & Graziano, C.
- Affiliations
- Medical Genetics Unit, AUSL Romagna, 47522 Cesena, Italy
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Rare Diseases Unit, Department of Pediatrics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Corresponding author
- Graziano, Claudio
- Venue
- Genes
- Publisher
- MDPI AG
- Published
- 2023-01-19
- Volume
- 14
- Issue
- 2
- Pages
- 258
- ISSN
- 2073-4425 (ISSN-L)
- PMC
- PMC9956891
- OpenAlex
- W4317425690
- Cited by
- 7
- References
- 30
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 1
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Genes (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (WT223718/Z/21/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Keywords
- SALL1, haploinsufficiency, mild phenotype, anal anomalies, skeletal abnormalities, developmental delay, nonsense-mediated mRNA decay, chromosomal microarray analysis
- MeSH terms
- Abnormalities, Multiple, Anus, Imperforate, Hearing Loss, Sensorineural, Humans, Phenotype, Syndrome, Thumb, Transcription Factors, Microarray Analysis, Comparative Genomic Hybridization, Haploinsufficiency
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