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PURPOSE: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but has not been clearly linked to neurodevelopmental disorders (NDD) 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 two 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 four 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 nervous system and for variable neurodevelopmental phenotypes.