Abstract
TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants' pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.
Original language | English |
---|---|
Pages (from-to) | 2384-2390 |
Number of pages | 7 |
Journal | American Journal of Medical Genetics, Part A |
Volume | 185 |
Issue number | 8 |
DOIs | |
Publication status | Published - Aug 2021 |
Keywords
- TCF7L2
- autism
- intellectual disability
- myopia
- neurodevelopmental disorder
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In: American Journal of Medical Genetics, Part A, Vol. 185, No. 8, 08.2021, p. 2384-2390.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder
AU - Dias, Caroline
AU - Pfundt, Rolph
AU - Kleefstra, Tjitske
AU - Shuurs-Hoeijmakers, Janneke
AU - Boon, Elles M.J.
AU - van Hagen, Johanna M.
AU - Zwijnenburg, Petra
AU - Weiss, Marjan M.
AU - Keren, Boris
AU - Mignot, Cyril
AU - Isapof, Arnaud
AU - Weiss, Karin
AU - Hershkovitz, Tova
AU - Iascone, Maria
AU - Maitz, Silvia
AU - Feichtinger, René G.
AU - Kotzot, Dieter
AU - Mayr, Johannes A.
AU - Ben-Omran, Tawfeg
AU - Mahmoud, Laila
AU - Pais, Lynn S.
AU - Walsh, Christopher A.
AU - Shashi, Vandana
AU - Sullivan, Jennifer A.
AU - Stong, Nicholas
AU - Lecoquierre, Francois
AU - Guerrot, Anne Marie
AU - Charollais, Aude
AU - Rodan, Lance H.
N1 - Funding Information: The authors thank the families for their invaluable participation in this study. For Family 11, we thank Muna Al-Saffar (research coordination), Ganeshwaran H. Mochida (neurological evaluation), Ramzi H. Nasir (developmental evaluation), and Lariza Rento and Samantha Kirkham (Sanger sequencing).We thank Abbe Lai for assistance with computational analysis. Some of this work was supported by PROGETTO GENE (GENE?Genomic analysis Evaluation NEtwork) founded by PROGETTI DI INNOVAZIONE IN AMBITO SANITARIO E SOCIO SANITARIO (BANDO EX DECRETO N. 2713 DEL 28/02/2018). Caroline Dias is supported in part by the National Institute of Mental Health (T32MH112510, Translational Post-doctoral Training in Neurodevelopment). For family 11, this project was supported by the Qatar National Research Fund (NPRP 5-175-3-051) (Tawfeg Ben-Omran, Laila Mahmoud, Christopher A. Walsh), as well as by NINDS 1R01 NS035129 to Christopher A. Walsh. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) funded by the National Human Genome Research Institute; the National Eye Institute; and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Christopher A. Walsh is an Investigator of the Howard Hughes Medical institute. One individual (P4) was ascertained in the Duke Genome Sequencing Clinic (Duke Protocol number 00032301). Funding for the Duke Genome Sequencing Clinic is supported by the Duke University Health System. Francois Lecoquierre and Anne-Marie Guerrot received funding from European Union and R?gion Normandie in the context of Recherche Innovation Normandie (RIN 2018). Europe is involved in Normandie with the European Regional Development Fund (ERDF). Funding Information: Duke University Health System; European Union and Région Normandie; National Human Genome Research Institute grant, Grant/Award Number: HG009141; National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute, Grant/Award Number: UM1 HG008900; National Institute of Mental Health (Translational Post‐doctoral Training in Neurodevelopment), Grant/Award Number: T32MH112510; NINDS, Grant/Award Number: NS035129; PROGETTO GENE, (GENE ‐ Genomic analysis Evaluation NEtwork) founded by PROGETTI DI INNOVAZIONE IN AMBITO SANITARIO E SOCIO SANITARIO (BANDO EX DECRETO N. 2713 DEL 28/02/2018); Qatar National Research Fund, Grant/Award Number: NPRP 5‐175‐3‐051 Funding information Funding Information: Some of this work was supported by PROGETTO GENE (GENE—Genomic analysis Evaluation NEtwork) founded by PROGETTI DI INNOVAZIONE IN AMBITO SANITARIO E SOCIO SANITARIO (BANDO EX DECRETO N. 2713 DEL 28/02/2018). Caroline Dias is supported in part by the National Institute of Mental Health (T32MH112510, Translational Post‐doctoral Training in Neurodevelopment). For family 11, this project was supported by the Qatar National Research Fund (NPRP 5‐175‐3‐051) (Tawfeg Ben‐Omran, Laila Mahmoud, Christopher A. Walsh), as well as by NINDS 1R01 NS035129 to Christopher A. Walsh. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) funded by the National Human Genome Research Institute; the National Eye Institute; and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Christopher A. Walsh is an Investigator of the Howard Hughes Medical institute. One individual (P4) was ascertained in the Duke Genome Sequencing Clinic (Duke Protocol number 00032301). Funding for the Duke Genome Sequencing Clinic is supported by the Duke University Health System. Francois Lecoquierre and Anne‐Marie Guerrot received funding from European Union and Région Normandie in the context of Recherche Innovation Normandie (RIN 2018). Europe is involved in Normandie with the European Regional Development Fund (ERDF). Publisher Copyright: © 2021 Wiley Periodicals LLC
PY - 2021/8
Y1 - 2021/8
N2 - TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants' pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.
AB - TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants' pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.
KW - TCF7L2
KW - autism
KW - intellectual disability
KW - myopia
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85105925781&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ajmg.a.62254
DO - https://doi.org/10.1002/ajmg.a.62254
M3 - Article
C2 - 34003604
SN - 1552-4825
VL - 185
SP - 2384
EP - 2390
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 8
ER -