LHX2 haploinsufficiency causes a variable neurodevelopmental disorder

Schmid CM, Gregor A, Costain G, Morel CF, Massingham L, Schwab J, Quélin C, Faoucher M, Kaplan J, Procopio R, Saunders CJ, Cohen AS, Lemire G, Sacharow S, O'Donnell-Luria A, Segal RJ, Kianmahd Shamshoni J, Schweitzer D, Ebrahimi-Fakhari D, Monaghan K, Palculict TB, Napier MP, Tao A, Isidor B, Moradkhani K, Reis A, Sticht H, Chung WK, Zweier C (2023)

Publication Type: Journal article

Publication year: 2023


Book Volume: 25

Article Number: 100839

Journal Issue: 7

DOI: 10.1016/j.gim.2023.100839


Purpose: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date. Methods: Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems. Results: Affected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction–mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants. Conclusion: We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes.

Authors with CRIS profile

Involved external institutions

How to cite


Schmid, C.M., Gregor, A., Costain, G., Morel, C.F., Massingham, L., Schwab, J.,... Zweier, C. (2023). LHX2 haploinsufficiency causes a variable neurodevelopmental disorder. Genetics in Medicine, 25(7). https://doi.org/10.1016/j.gim.2023.100839


Schmid, Cosima M., et al. "LHX2 haploinsufficiency causes a variable neurodevelopmental disorder." Genetics in Medicine 25.7 (2023).

BibTeX: Download