Abstract
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.
Keywords
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Article info
Publication history
Published online: April 10, 2023
Accepted:
April 5,
2023
Received in revised form:
April 3,
2023
Received:
November 16,
2022
Footnotes
Cosima M. Schmid and Anne Gregor contributed equally.
Wendy K. Chung and Christiane Zweier contributed equally.
Identification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
