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Cited by 185Genomics and Rare DiseasesCongenital limb and hand anomaliesCongenital heart defects research

Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy

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Kohlhase, J, Schubert, L, Liebers, M, Rauch, A, Becker, K, Mohammed, S N, Newbury-Ecob, R, Reardon, W·2003·Journal of Medical Genetics
DOI 10.1136/jmg.40.7.473PMC PMC1735528
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Abstract

We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of “thalidomide embryopathy” might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.

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Crossref · 10.1136/jmg.40.7.473

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  • HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development.

    “HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development”

    From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [30]

    The introduction and Discussion link SALL4 mutations to congenital limb and other malformations, supporting its implication in development. The paper does not address HIC1, HIC2, GZF1, OSR1, or OSR2, so it does not support the claim about all six genes (searched for those gene names). (LLM, conf=0.88)

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  • HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 could contribute to developmental abnormalities in fetuses exposed to thalidomide.

    “and could contribute to developmental abnormalities in fetuses exposed to thalidomide (25–30).”

    From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [30]

    The Discussion (page unavailable) supports SALL4 as a cause of developmental abnormalities in a family previously thought to have thalidomide embryopathy. It does not address HIC1, HIC2, GZF1, OSR1, or OSR2. It also argues that the family's phenotype was likely misdiagnosed as thalidomide embryopathy, rather than showing that these genes contribute to abnormalities caused by thalidomide exposure. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • DRRS and HOS have large phenotypic overlaps with thalidomide embryopathy.

    “Remarkably, both DRRS and HOS have large phenotypic overlaps with thalidomide embryopathy (Kohlhase et al., 2003)”

    From Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome (2018) · cites this paper as Kohlhase et al., 2003

    The case reports describe a patient diagnosed with thalidomide embryopathy on the basis of his limb abnormalities, while other SALL4-affected patients were initially diagnosed with Holt-Oram syndrome. The Discussion says the presumed thalidomide case was more likely a SALL4-related phenotype. These passages support clinical resemblance, but do not establish a large phenotypic overlap of both DRRS and HOS with confirmed thalidomide embryopathy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Several ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.

    “Several of the ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.”

    From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [30]

  • Heterozygous loss-of-function mutations in SALL4 cause Duane Radial Ray syndrome (DRRS)/Okihiro syndrome and are mutated in some patients with Holt-Oram syndrome (HOS).

    “Strikingly, human genetic research has shown that familial loss of function (LOF) mutations in SALL4 are causatively linked to the clinical syndromes, Duane Radial Ray syndrome (DRRS) also known as Okihiro syndrome, and mutated in some patients with Holt-Oram syndrome (HOS).”

    From Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome (2018) · cites this paper as Kohlhase et al., 2003

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Cites

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Research works printed but not linked: 3

  1. [5]5. Kohlhase J. SALL1 mutations in Townes-Brocks syndrome and related disorders. Hum Mut 2000;16:460-6.
  2. [13]13. Yang S, Sherman S, Derstine J, Schonberg S. Holt-Oram gene may be on chromosome 20. Pediatr Res 1990;27:137A.
  3. [16]16. Fraisse J, Bertheas MF, Frere F, Lauras B, Rolland MO, Brizard CP. Un nouveau syndrome: del(20)(q13-qter). Localisation segmentaire de gene de l'adenosine deaminase (ADA). Ann Genet 1981;24:216-19.

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Authors
Kohlhase, J., Schubert, L., Liebers, M., Rauch, A., Becker, K., Mohammed, S. N., Newbury-Ecob, R., & Reardon, W.
Affiliations
  • University of Göttingen (DE)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Northwick Park Hospital (GB)
  • Guy's Hospital (GB)
  • St Michael's Hospital (GB)
  • Children's Health Ireland at Crumlin (IE)
Corresponding author
Kohlhase, J
ORCID
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2003-07
Volume
40
Issue
7
Pages
473-478
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmg.40.7.473
PMC
PMC1735528
OpenAlex
W2142039491
Cited by
185
References
28
Citations by year
2026: 3 · 2025: 3 · 2024: 12 · 2023: 4 · 2022: 10 · 2021: 5 · 2020: 10 · 2019: 7 · 2018: 10 · 2017: 5 · 2016: 11 · 2015: 8 · 2014: 12 · 2013: 7 · 2012: 6
FWCI
5.13
Type
journal article
Language
en
Open access
Locations
  • Journal of Medical Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • GRO (submittedVersion)
Funders
Hospital for Sick Children
Topics
  • 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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
SALL4, Holt-Oram syndrome, thalidomide embryopathy, zinc finger transcription factor, TBX5, novel mutations, genotype-phenotype overlap, congenital heart disease, limb malformations
MeSH terms
Abnormalities, Multiple, Base Sequence, Chromosomes, Human, Pair 20, DNA, DNA Mutational Analysis, Duane Retraction Syndrome, Family Health, Female, Fetal Diseases, Hand Deformities, Congenital, Heart Septal Defects, Atrial, Humans, Kidney, Male, Mutation, Pedigree, Phenotype, Thalidomide, Thumb, Transcription Factors

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