Rithvik Gunda

Background: Mutations in the MEIS2 gene, located on chromosome 15q14, are associated with a triad of developmental conditions: cleft lip and/or palate, congenital heart defects, and intellectual impairment. MEIS2 is a member of the TALE (Three Amino Acid Loop Extension) homeobox gene family and acts as a transcription factor involved in early embryonic development. It has a very specific function in the regulation of neural crest cell migration and differentiation that forms craniofacial structures, cardiac tissue, and neural tracts. Haploinsufficiency of MEIS2, in which a single copy of the gene is inactivated or deleted, decreases its functional protein levels and causes disturbances in multiple developmental systems. Patients who carry MEIS2 variants experience a full spectrum of symptoms from delayed learning to outright heart defects and orofacial malformations.^{1, 2, 4}

Objective: The aim of this review was to explore the mechanisms in which loss-of-function variants of MEIS2 produce the general triad of structural and cognitive abnormalities based on recent literature and from genetic, molecular, and clinical points of view.

Search Methods: PubMed was searched for publications between the years 2017 and 2023. The keywords used were “MEIS2,” “cleft palate,” “congenital heart disease,” “neurodevelopmental delay,” and “15q14 deletion.”

Results: MEIS2 plays a crucial role in the palatal shelf fusion occurring in embryogenesis. Without it, neural crest cells fail to populate the maxillary area properly, which results in structural abnormalities like cleft palate or bifid uvula.^{1, 3} Studies such as those conducted by Verheije et al. reported that more than 70% of individuals who suffered from MEIS2 haploinsufficiency exhibited some palatal abnormality.¹ Cardiac abnormalities are also frequent, including ventricular and atrial septal defects as well as in some instances even more critical defects like persistent truncus arteriosus.^{1, 6} MEIS2 controls genes involved in cardiogenesis and also affects cardiac progenitor cell development when absent.^{2, 6} Within the brain, MEIS2 aids in neuron differentiation and maturation, especially in areas like the cerebral cortex and striatum.⁵ Loss-of-function mutations result in intellectual delay, attention-deficit disorder, and autism spectrum disorder features.^{1, 4} Animal models recapitulate human experience as cranial nerve development defects and profound brain growth and function deficits result from MEIS2 loss-of-function mutations.⁶

Conclusion: Heterozygous MEIS2 variants cause a multifaceted developmental syndrome affecting facial anatomy, heart development, and intellectual function. While treatment now focuses on treating single symptoms—e.g., cleft palate surgery or congenital heart correction—there’s a clear demand for holistic care approaches addressing the entire clinical profile.^{1, 4} Genetic counseling, early diagnosis and development screening, and treatment planning form a core set of interventions likely to enhance outcomes. Future efforts examining the correlation between specific MEIS2 mutations and severity of phenotype may inform personalized clinical and therapeutic plans. Understanding MEIS2 function in neural crest development and embryonic development will remain critical for the discovery of novel means of patient and family care in this syndrome.^{1, 2, 4, 6}

Works Cited:

1. Verheije R, Kupchik GS, Isidor B, et al. Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability. Eur J Hum Genet. 2018;27(2):278-290. doi:10.1038/s41431-018-0281-5
2. Miksiunas R, Mobasheri A, Bironaite D. Homeobox Genes and Homeodomain Proteins: New Insights into Cardiac Development, Degeneration and Regeneration. Adv Exp Med Biol. 2019:155-178. doi:10.1007/5584_2019_349
3. Europe PMC. Europepmc.org. Published 2020. Accessed February 19, 2025. https://europepmc.org/article/pmc/7513377
4. Leung RF, George AM, Roussel EM, Faux MC, Wigle JT, Eisenstat DD. Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes. Front Neurosci. 2022;16. doi:10.3389/fnins.2022.843794
5. Larsen KB, Lutterodt MC, Laursen H, et al. Spatiotemporal Distribution of PAX6 and MEIS2 Expression and Total Cell Numbers in the Ganglionic Eminence in the Early Developing Human Forebrain. Dev Neurosci. 2010;32(2):149-162. doi:10.1159/000297602
6. Machon O, Masek J, Machonova O, Krauss S, Kozmik Z. Meis2 is essential for cranial and cardiac neural crest development. BMC Dev Biol. 2015;15(1). doi:10.1186/s12861-015-0093-6