Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep;108(3):279-291.
doi: 10.1111/cge.14746. Epub 2025 Apr 23.

Expansion of the Genotypic and Phenotypic Spectrum of SETD5 Disorder Using Data From the National Brain Gene Registry

Nora C Callahan  1 , Sonal Mahida  2 , Abigail Sveden  2 , Meg Quinn  2 , Maya Chopra  2 , Siddharth Srivastava  2 ; Brain Gene Registry Consortium
Collaborators, Affiliations

Expansion of the Genotypic and Phenotypic Spectrum of SETD5 Disorder Using Data From the National Brain Gene Registry

Nora C Callahan et al. Clin Genet. 2025 Sep.

Abstract

Haploinsufficiency of SETD5, which facilitates gene transcription and histone modification, causes intellectual disability. However, the full phenotypic spectrum of SETD5 Disorder is not well characterized. We summarized clinical features of participants with SETD5 Disorder enrolled in the National Brain Gene Registry (BGR). We analyzed data from 13 individuals with a molecular diagnosis of SETD5 Disorder, ages 2-37 years, using data from electronic health records, standardized surveys, and direct assessments. We also determined the number of participants for whom 10 pre-selected clinical features were present based on ICD-10 billing codes in comparison to manual review of clinical documentation. In the cohort, there were 11 unique pathogenic/likely pathogenic variants in 13 individuals from 11 different families. Of these 11 unique variants, 6 were nonsense, 4 were frameshift, and one was splice site. Participants in our cohort had features not previously reported, including brain and musculoskeletal abnormalities. One participant had cerebral palsy. For the 10 pre-selected clinical features, we showed satisfactory representation of these features by ICD-10 billing codes. This report highlights novel genotype and phenotype associations with SETD5 Disorder. Examination of larger patient cohorts with SETD5 Disorder is needed to evaluate the true prevalence of these medical conditions in this disorder.

Keywords: SETD5; autism; genotypic expansion; intellectual disability; phenotypic expansion.

PubMed Disclaimer

References

    1. D. Grozeva, K. Carss, O. Spasic‐Boskovic, et al., “De Novo Loss‐Of‐Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability,” American Journal of Human Genetics 94, no. 4 (2014): 618–624, https://doi.org/10.1016/j.ajhg.2014.03.006.
    1. A. Kuechler, A. M. Zink, T. Wieland, et al., “Loss‐Of‐Function Variants of SETD5 Cause Intellectual Disability and the Core Phenotype of Microdeletion 3p25.3 Syndrome,” European Journal of Human Genetics 23, no. 6 (2015): 753–760, https://doi.org/10.1038/ejhg.2014.165.
    1. E. Deliu, N. Arecco, J. Morandell, et al., “Haploinsufficiency of the Intellectual Disability Gene SETD5 Disturbs Developmental Gene Expression and Cognition,” Nature Neuroscience 21, no. 12 (2018): 1717–1727, https://doi.org/10.1038/s41593‐018‐0266‐2.
    1. A. B. Osipovich, R. Gangula, P. G. Vianna, and M. A. Magnuson, “Setd5 Is Essential for Mammalian Development and the Co‐Transcriptional Regulation of Histone Acetylation,” Development 143, no. 24 (2016): 4595–4607, https://doi.org/10.1242/dev.141465.
    1. Z. Powis, K. D. Farwell Hagman, C. Mroske, et al., “Expansion and Further Delineation of the SETD5 Phenotype Leading to Global Developmental Delay, Variable Dysmorphic Features, and Reduced Penetrance,” Clinical Genetics 93, no. 4 (2018): 752–761, https://doi.org/10.1111/cge.13132.

LinkOut - more resources