LHX2 haploinsufficiency causes a variable neurodevelopmental disorder.
Genet Med
; 25(7): 100839, 2023 Jul.
Article
em En
| MEDLINE
| ID: mdl-37057675
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Transtornos do Neurodesenvolvimento
/
Transtorno do Espectro Autista
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Deficiência Intelectual
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article