. 2019 Sep;21(9):2036-2042.

doi: 10.1038/s41436-019-0454-9. Epub 2019 Feb 11.

Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature

Erin Torti¹, Boris Keren², Elizabeth E Palmer^{3

4}, Zehua Zhu⁵, Alexandra Afenjar^{6

7

8}, Ilse J Anderson⁹, Marisa V Andrews¹⁰, Celia Atkinson¹¹, Margaret Au¹², Susan A Berry¹³, Kevin M Bowling¹⁴, Jackie Boyle³, Julien Buratti², Sara S Cathey¹⁵, Perrine Charles^{2

16

17}, Benjamin Cogne^{18

19}, Thomas Courtin², Luis F Escobar²⁰, Sabra Ledare Finley²¹, John M Graham Jr¹², Dorothy K Grange¹⁰, Delphine Heron^{2

6

16

17}, Stacy Hewson¹¹, Susan M Hiatt¹⁴, Kathleen A Hibbs²², Parul Jayakar²³, Louisa Kalsner^{24

25}, Lise Larcher², Gaetan Lesca^{26

27}, Paul R Mark²⁸, Kathryn Miller²⁹, Caroline Nava^{2

30}, Mathilde Nizon^{18

19}, G Shashidhar Pai³¹, John Pappas³², Gretchen Parsons²⁸, Katelyn Payne³³, Audrey Putoux^{26

27}, Rachel Rabin³², Isabelle Sabatier³⁴, Marwan Shinawi¹⁰, Natasha Shur²⁹, Steven A Skinner¹⁵, Stephanie Valence³⁵, Hannah Warren¹⁵, Sandra Whalen³⁶, Amy Crunk⁵, Ganka Douglas⁵, Kristin G Monaghan⁵, Richard E Person⁵, Rebecca Willaert⁵, Benjamin D Solomon⁵, Jane Juusola³⁷

Affiliations

¹ GeneDx, Gaithersburg, MD, USA. etorti@genedx.com.
² Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
³ Genetics of Learning Disability Service, Hunter New England Health, Waratah, NSW, Australia.
⁴ Australia School of Women's' and Children' Health, University of New South Wales, Sydney, NSW, Australia.
⁵ GeneDx, Gaithersburg, MD, USA.
⁶ Département de génétique et embryologie médicale, Hôpital Trousseau, Assistance publique-Hôpitaux de Paris, Paris, France.
⁷ Centre de Référence malformations et maladies congénitales du cervelet, Paris, France.
⁸ Sorbonne Universités, GRC ConCer-LD, Hôpital Armand Trousseau, Paris, France.
⁹ Department of Medicine, Division of Genetics, the University of Tennessee Graduate School of Medicine, University Genetics, Knoxville, TN, USA.
¹⁰ Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹¹ Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹² Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³ Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
¹⁴ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
¹⁵ Greenwood Genetic Center, Greenwood, SC, USA.
¹⁶ Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.
¹⁷ Sorbonne Université, GRC "Déficience Intellectuelle et Autisme", Paris, France.
¹⁸ CHU Nantes, Service de Génétique Médicale, Nantes, France.
¹⁹ l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.
²⁰ St. Vincent Hospital and Health Services, Indianapolis, IN, USA.
²¹ University Genetics, University of Tennessee Medical Center, Knoxville, TN, USA.
²² University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.
²³ Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA.
²⁴ Connecticut Children's Medical Center, Farmington, CT, USA.
²⁵ School of Medicine, University of Connecticut, Farmington, CT, USA.
²⁶ Department of Medical Genetics, Lyon University Hospitals, Lyon, France.
²⁷ Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Claude Bernard Lyon I University, Lyon, France.
²⁸ Spectrum Health Medical Genetics, Grand Rapids, MI, USA.
²⁹ Albany Medical Center, Albany, NY, USA.
³⁰ Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, Paris, France.
³¹ Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
³² Department of Pediatrics, New York University School of Medicine, New York, NY, USA.
³³ Riley Hospital for Children, Indianapolis, IN, USA.
³⁴ Department of Pediatric Neurology, Women Mother and Children Hospital, Lyon University Hospitals, Lyon, France.
³⁵ Service de neuropédiatrie, Hôpital Trousseau, Assistance publique-Hôpitaux de Paris, Paris, France.
³⁶ Unité Fonctionnelle de génétique clinique, Hôpital Armand Trousseau, Assistance publique-Hôpitaux de Paris, Centre de Référence des anomalies du développement et syndromes malformatifs, Paris, France.
³⁷ GeneDx, Gaithersburg, MD, USA. jjuusola@genedx.com.

PMID: 30739909
PMCID: PMC7171701
DOI: 10.1038/s41436-019-0454-9

Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature

Erin Torti et al. Genet Med. 2019 Sep.

. 2019 Sep;21(9):2036-2042.

doi: 10.1038/s41436-019-0454-9. Epub 2019 Feb 11.

Authors

Affiliations

¹ GeneDx, Gaithersburg, MD, USA. etorti@genedx.com.
² Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
³ Genetics of Learning Disability Service, Hunter New England Health, Waratah, NSW, Australia.
⁴ Australia School of Women's' and Children' Health, University of New South Wales, Sydney, NSW, Australia.
⁵ GeneDx, Gaithersburg, MD, USA.
⁶ Département de génétique et embryologie médicale, Hôpital Trousseau, Assistance publique-Hôpitaux de Paris, Paris, France.
⁷ Centre de Référence malformations et maladies congénitales du cervelet, Paris, France.
⁸ Sorbonne Universités, GRC ConCer-LD, Hôpital Armand Trousseau, Paris, France.
⁹ Department of Medicine, Division of Genetics, the University of Tennessee Graduate School of Medicine, University Genetics, Knoxville, TN, USA.
¹⁰ Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹¹ Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹² Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³ Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
¹⁴ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
¹⁵ Greenwood Genetic Center, Greenwood, SC, USA.
¹⁶ Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.
¹⁷ Sorbonne Université, GRC "Déficience Intellectuelle et Autisme", Paris, France.
¹⁸ CHU Nantes, Service de Génétique Médicale, Nantes, France.
¹⁹ l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.
²⁰ St. Vincent Hospital and Health Services, Indianapolis, IN, USA.
²¹ University Genetics, University of Tennessee Medical Center, Knoxville, TN, USA.
²² University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.
²³ Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA.
²⁴ Connecticut Children's Medical Center, Farmington, CT, USA.
²⁵ School of Medicine, University of Connecticut, Farmington, CT, USA.
²⁶ Department of Medical Genetics, Lyon University Hospitals, Lyon, France.
²⁷ Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Claude Bernard Lyon I University, Lyon, France.
²⁸ Spectrum Health Medical Genetics, Grand Rapids, MI, USA.
²⁹ Albany Medical Center, Albany, NY, USA.
³⁰ Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, Paris, France.
³¹ Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
³² Department of Pediatrics, New York University School of Medicine, New York, NY, USA.
³³ Riley Hospital for Children, Indianapolis, IN, USA.
³⁴ Department of Pediatric Neurology, Women Mother and Children Hospital, Lyon University Hospitals, Lyon, France.
³⁵ Service de neuropédiatrie, Hôpital Trousseau, Assistance publique-Hôpitaux de Paris, Paris, France.
³⁶ Unité Fonctionnelle de génétique clinique, Hôpital Armand Trousseau, Assistance publique-Hôpitaux de Paris, Centre de Référence des anomalies du développement et syndromes malformatifs, Paris, France.
³⁷ GeneDx, Gaithersburg, MD, USA. jjuusola@genedx.com.

PMID: 30739909
PMCID: PMC7171701
DOI: 10.1038/s41436-019-0454-9

Abstract

Purpose: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients.

Methods: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information.

Results: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports.

Conclusion: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

Keywords: TCF20; autism; developmental delay; exome; intellectual disability.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST NOTIFICATION

E.T., A.C., G.D., J.J., K.G.M., R.E.P., R.W., B.D.S., and Z.Z. are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc.

Figures

**Figure 1:. *TCF20* variants.**
Upper panel: Genomic structure of the *TCF20* gene. Exons are shown to scale with the coding sequence in color and untranslated regions in black. The position of the first coding nucleotide is shown in exon 2, and numbers in other black boxes indicate cDNA numbering of the last nucleotides of exon boundaries or last nucleotide of stop codons. Introns are depicted by black horizontal dashed line and sizes are not indicated. Novel variants are represented in black stars, and previously reported variants are represented in red circles, blue squares, green triangles, and purple pentagons. *De novo* novel variants are italicized. Lower panel: Diagram representing the TCF20 protein with previously annotated domains. TAD, trans activation domain. Q1/Q2, glutamine-rich stretches. P1-P3, PEST domains. N1-N3, nuclear localisation signals. MD, minimal DNA binding domain. ZNF, zinc finger domain. ePHD/ADD, extended plant homeodomain/ATRX-DNMT3-DNMT3L.

**Figure 2:. Facial appearance of individuals with variants in *TCF20*.**
While minor craniofacial anomalies are noted in the majority of patients, a specific gestalt has not emerged. A, Patient 2. B, Patient 11. C, Patient 21. D, Patients 17a-c.

See this image and copyright information in PMC

References

1. Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual disability, and autism. N Engl J Med 2012;366(8):733–43. - PMC - PubMed
1. Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet 2016;17(1):9–18. - PubMed
1. Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 2014;312(18):1880–1887. - PMC - PubMed
1. Farwell KD, Shahmirzadi L, El-Khechen D, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 2015;17(7):578–586. - PubMed
1. Fitzgerald TW, Gerety SS, Jones WD, et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature 2015;519(7542):223–228. - PMC - PubMed

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Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature

Affiliations

Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases