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.
APA:
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://dx.doi.org/10.1016/j.gim.2023.100839
MLA:
Schmid, Cosima M., et al. "LHX2 haploinsufficiency causes a variable neurodevelopmental disorder." Genetics in Medicine 25.7 (2023).
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