TFE3‐associated neurodevelopmental disorder: A distinct recognizable syndrome
Abstract
The transcription factor for immunoglobulin heavy‐chain enhancer 3 (TFE3) gene encodes a transcription factor that regulates embryonic stem cell (ESC) differentiation. Its phosphorylation by the lysosomal Rag GTPase signaling pathway leads to cytoplasmic sequestration and inactivation promoting ESC differentiation and exit from pluripotency. Somatic translocations of this X‐linked gene cause papillary renal cell carcinoma in which nuclear accumulation of the TFE3 oncoprotein is one of the most significant histopathologic characteristics. Early this year, Villegas et al. identified missense mutations in a TFE3 domain required for cytoplasmic inactivation as potentially causal for a mosaic human developmental disorder. They published five patients with de novo TFE3 nonsynonymous missense variants, four females and one male, with severe intellectual disability (5/5), coarse facial features (4/5), and Blaschkoid pigmentary mosaicism (4/5). The only male described has somatic mosaicism. All patients had normal brain Magnetic Resonance Imagings (MRIs). We present two unrelated females with this distinctive phenotype including the above triad along with other features not previously well described. Both were found to have de novo heterozygous variants in TFE3 on whole exome sequencing, one nonsynonymous missense, and one canonical splice site variant, thereby expanding the phenotypic and mutational spectrum for this disorder. Interestingly, due to significant coarsening of the facial features, both patients were initially thought to have a lysosomal storage disorder but enzyme screening and brain MRIs were negative.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Six of the 28 novel developmental-disorder-associated genes are corroborated by OMIM entries or publications, including TFE3.
“Six of the 28 novel DD-associated genes are corroborated by OMIM entries or publications, including TFE3 11,12 which was described in two recent publications.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [12]
Cites
Prevalence and architecture of de novo mutations in developmental disorders
Study, D. D. D. (2017) · Nature · doi:10.1038/nature21062 · Cited by 1,480 · see citing works
Clark, J., Lu, Y., Sidhar, S. K., Parker, C. C., Gill, S., Smedley, D. P., Hamoudi, R., Linehan, W. M., SHIPLEY, J. M., & Cooper, C. S. (1997) · Oncogene · doi:10.1038/sj.onc.1201394 · Cited by 343 · see citing works
The lysosome as a command-and-control center for cellular metabolism
Lim, C.-Y., & Zoncu, R. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201607005 · Cited by 274 · see citing works
Slade, L., & Pulinilkunnil, T. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0320 · Cited by 149 · see citing works
TFE3 regulates whole‐body energy metabolism in cooperation with TFEB
Pastore, N., Vainshtein, A., Klisch, T. J., Armani, A., Huynh, T., Herz, N. J., Polishchuk, E. V., Sandri, M., & Ballabio, A. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201607204 · Cited by 142 · see citing works
Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3
Villegas, F., Lehalle, D., Mayer, D., Rittirsch, M., Stadler, M. B., Zinner, M., Olivieri, D., Vabres, P., Duplomb-Jego, L., De Bont, E. S. J. M., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.11.021 · Cited by 110 · see citing works
Yin, X., Wang, B., Gan, W., Zhuang, W., Xiang, Z., Han, X., & Li, D. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1101-7 · Cited by 62 · see citing works
Ragulator—a multifaceted regulator of lysosomal signaling and trafficking
Colaço, A., & Jäättelä, M. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201710039 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Evidence for 28 genetic disorders discovered by combining healthcare and research data
Kaplanis, J., Samocha, K. E., Wiel, L., Zhang, Z., Arvai, K. J., Eberhardt, R. Y., Gallone, G., Lelieveld, S. H., Martin, H. C., McRae, J. F., et al. (2020) · Nature · doi:10.1038/s41586-020-2832-5 · Cited by 615 · see citing works
MiT/TFE Family of Transcription Factors: An Evolutionary Perspective
Spina, M. L., Contreras, P. S., Rissone, A., Meena, N. K., Jeong, E., & Martina, J. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.609683 · Cited by 91 · see citing works
A central role for regulated protein stability in the control of TFE3 and MITF by nutrients
Nardone, C., Palanski, B. A., Scott, D. C., Timms, R. T., Barber, K. W., Gu, X., Mao, A., Leng, Y., Watson, E. V., Schulman, B. A., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.013 · Cited by 50 · see citing works
Kaplanis, J., Samocha, K. E., Wiel, L., Zhang, Z., Arvai, K. J., Eberhardt, R. Y., Gallone, G., Lelieveld, S. H., Martin, H. C., McRae, J. F., et al. (2019) · doi:10.1101/797787 · Cited by 36 · see citing works
Lang, M., Pramstaller, P. P., & Pichler, I. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00555-7 · Cited by 34 · see citing works
TFE3-Rearranged Tumors of the Kidney: An Emerging Conundrum
Caliò, A., Marletta, S., Brunelli, M., Antonini, P., Martelli, F. M., Marcolini, L., Stefanizzi, L., & Martignoni, G. (2024) · Cancers · doi:10.3390/cancers16193396 · Cited by 17 · see citing works
Lehalle, D., Vabres, P., Sorlin, A., Bierhals, T., Avila, M., Carmignac, V., Chevarin, M., Torti, E. E., Abe, Y., Bartolomaeus, T., et al. (2020) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2019-106508 · Cited by 16 · see citing works
TFE3 Rearrangement and Expression in Renal Cell Carcinoma
Kmeid, M., & Akgül, M. (2022) · International Journal of Surgical Pathology · doi:10.1177/10668969221108517 · Cited by 14 · see citing works
Galea, L. A., Hildebrand, M. S., Boys, A., Joy, C., Chee, J. B. L., & White, G. (2022) · Pathology · doi:10.1016/j.pathol.2022.02.012 · Cited by 4 · see citing works
Pigmentary Mosaicism: An Overview
Colmant, C., Legius, E., Cattaert, N., & Morren, M. (2025) · JEADV Clinical Practice · doi:10.1002/jvc2.70048 · Cited by 2 · see citing works
Sofronova, V., Gurinova, E., Петухова, Д. А., Fukamatsu, H., Yamamoto, T., Aoyama, Y., Иннокентьевна, Г. П., Moskvitin, G., Ivanova, R., Саввина, М. Т., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065647 · Cited by 1 · see citing works
Satterstrom, F. K., Jodeiry, K., Mahjani, B., Hatem, G., Park, S. J., Klei, L., Fu, J. M., Wigdor, E. M., Betancur, C., Daly, M. J., et al. (2026) · medRxiv · doi:10.64898/2026.05.04.26352380 · Cited by 1 · see citing works
Vastrad, B. M., & Vastrad, C. M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.24.461631
Zhang, Q., Axelbaum, A., Furuya, K. N., & Gulliver, J. (2024) · Pediatric and Developmental Pathology · doi:10.1177/10935266241298805
- Authors
- Diaz, J., Berger, S., & Leon, E.
- Affiliations
- Children's National (US)
- Corresponding author
- Leon, Eyby
- Venue
- American Journal of Medical Genetics Part A
- Publisher
- Wiley
- Published
- 2019-12-12
- Volume
- 182
- Issue
- 3
- Pages
- 584-590
- ISSN
- 1552-4825 (ISSN-L)
- 1552-4833
- OpenAlex
- W2994926002
- Cited by
- 14
- References
- 8
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 1
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Medical Genetics Part A (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- TFE3, neurodevelopmental disorders, missense mutations, splice site mutation, intellectual disability, coarse facial features, somatic mosaicism, transcription factors, phenotypic spectrum, de novo mutations
- MeSH terms
- Exome Sequencing, Child, Female, Humans, Male, Intellectual Disability, Phenotype, Lysosomal Storage Diseases, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Neurodevelopmental Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
