Last updated:
6/5/2023
Years published: 2023
NORD gratefully acknowledges Melissa Denish, MD Candidate, Sidney Kimmel Medical College and David Fajgenbaum, MD, MBA, MSc, University of Pennsylvania, for the preparation of this report.
TCF7L2-related neurodevelopmental disorder (TRND) is a newly discovered disorder caused by a change (variant or mutation) in the TCF7L2 gene. This mutation may be responsible for developmental delays in childhood, intellectual disability, autism, myopia, ADHD, abnormal physical features and other problems. There is a wide spectrum of severity for individuals affected with TRND. Many of the symptoms of TRND overlap with other neurodevelopmental disorders. TRND must be diagnosed with a genetic test and cannot be diagnosed by symptoms alone.
There is a wide spectrum of severity for individuals affected with TRND. Affected children tend to have developmental delays such as delayed speech and motor milestones. Some children may grow up to have average intellectual abilities, while others may have mild/moderate intellectual disability. Some individuals with TRND may also have autism spectrum disorder (ASD), social communication deficits, speech-language impairment and/or attention-deficit/hyperactivity disorder (ADHD). About half of those with the mutation may have nearsightedness (myopia) or vision impairments. Some children have been reported to have abnormal physical features such as a curved spine (scoliosis) and abnormal chest shape. However, the significance of these findings is still unknown. Many of the symptoms of TRND overlap with other neurodevelopmental disorders.
Autism spectrum disorder (ASD) is characterized by lack of interest, repetitive behaviors and issues with social interaction and communication. Patients may also have problems with eye contact and other nonverbal social communications, as well as difficulty making and maintaining relationships with peers. Early symptoms of ASD (at about 1-2 years) are poor eye contact, limited response to name, little gesturing and regression of language skills. Toddlers may demonstrate little pretend play and very intense interests. Children may have trouble with literal thinking and emotions.
TCF7L2-related neurodevelopmental disorder is caused by a change (variant or mutation) in the TCF7L2 gene. Mutations are nearly always de novo, which means that the mutation is present in the child but not in the parents. Because of the mutation in this gene, the protein product of the gene (a transcription factor) is either made incorrectly or not formed at all. Transcription factors are DNA-binding factors that regulate the amount of protein made in cells. Due to the lack of this protein, which is critical for brain development, patients develop the symptoms of TRND. There is currently no understood link between the mutation and the specific symptoms of TRND.
TRND follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
There are no known risk factors or populations that are affected at increased rates. It appears that TRND may be more common in males.
A diagnosis of TRND may be suspected based on clinical signs and symptoms such as delayed development and/or difficulty with speech, motor skills, behavior, learning or other neurological functions, as well as autism, ADHD, intellectual disability and vision/hearing impairments.
A diagnosis of TRND is confirmed by genetic testing that shows a likely pathogenic mutation in the TCF7L2 gene. The TCF7L2 gene is not included in most targeted gene panels for autism or myopia, so whole exome or whole genome testing is usually required to make a diagnosis. Genetic testing may be warranted if a child has diagnoses of autism and myopia.
There are currently no established medical treatments for TCF7L2-related neurodevelopmental disorder. Behavioral therapies may be helpful for some patients. A multidisciplinary team of care providers for children with TRND may include a genetic counselor or geneticist, developmental psychologist, speech and physical therapists and learning specialists.
Recently, a small study of folinic acid was found to potentially play a role in improving symptoms of autism. Further research is needed.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Del Bosque-Plata L, Hernández-Cortés EP, Gragnoli C. The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes. J Cell Physiol. 2022;237(1):301-312. doi:10.1002/jcp.30581
Dias C, Pfundt R, Kleefstra T, et al. De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder. Am J Med Genet A. 2021;185(8):2384-2390. doi:10.1002/ajmg.a.62254
Del Bosque-Plata L, Martínez-Martínez E, Espinoza-Camacho MÁ, Gragnoli C. The role of TCF7L2 in type 2 diabetes. Diabetes. 2021;70(6):1220-1228. doi:10.2337/db20-0573
Hodges H, Fealko C, Soares N. Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation. Transl Pediatr. 2020;9(Suppl 1):S55-S65. doi:10.21037/tp.2019.09.09
Frye RE, Slattery J, Delhey L, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018;23(2):247-256. doi:10.1038/mp.2016.168
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