Human Gene Module / Chromosome 9 / LHX2

LHX2LIM homeobox 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
20 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
9q33.3
Associated Disorders
-
Relevance to Autism

A de novo frameshift variant and several de novo missense variants in the LHX2 gene have been identified in ASD probands from the Autism Sequencing Consortium and the SPARK cohort (Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022). Schmid et al., 2023 reported 19 individuals from 18 families, including the three ASD probands from the SPARK cohort, with LHX2 variation and presenting with a variable neurodevelopmental disorder characterized by developmental delay, autism spectrum disorder and other behavioral abnormalities, variable intellectual disability, and microcephaly; four of the LHX2 missense variants identified in affected individuals, including one that was observed in a SPARK ASD proband, were shown experimentally to result in nucleolar accumulation, impaired interaction with co-factor LDB1, and/or reduced transcriptional activation by luciferase assay.

Molecular Function

This gene encodes a protein belonging to a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may function as a transcriptional regulator. The protein can recapitulate or rescue phenotypes in Drosophila caused by a related protein, suggesting conservation of function during evolution.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to LHX2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Support - Zhou X et al. (2022) Yes -
3 Support - Trost B et al. (2022) Yes -
4 Primary - Schmid CM et al. (2023) No ASD or autistic features, ADHD, ID
5 Support - Suhua Chang et al. () Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.621C>A p.Asn207Lys missense_variant De novo - - 37057675 Schmid CM et al. (2023)
c.880A>G p.Lys294Glu missense_variant De novo - - 37057675 Schmid CM et al. (2023)
- - copy_number_loss Unknown Not maternal Unknown 37057675 Schmid CM et al. (2023)
c.589A>T p.Lys197Ter stop_gained De novo - Simplex 37057675 Schmid CM et al. (2023)
c.639C>A p.Tyr213Ter stop_gained De novo - Simplex 37057675 Schmid CM et al. (2023)
c.938G>A p.Trp313Ter stop_gained De novo - Simplex 37057675 Schmid CM et al. (2023)
c.238T>A p.Cys80Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.123C>T p.Thr41= synonymous_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.644A>G p.Asn215Ser missense_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.809G>T p.Arg270Leu missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.437G>A p.Cys146Tyr missense_variant De novo - Simplex 37057675 Schmid CM et al. (2023)
c.948C>G p.Asn316Lys missense_variant De novo - Simplex 37057675 Schmid CM et al. (2023)
c.953G>T p.Arg318Leu missense_variant Familial Maternal - 37057675 Schmid CM et al. (2023)
c.289_293del p.Asp97Ter frameshift_variant Unknown - Simplex 37057675 Schmid CM et al. (2023)
c.187del p.Arg63AlafsTer66 frameshift_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.272dup p.Thr92HisfsTer8 frameshift_variant De novo - Simplex 37057675 Schmid CM et al. (2023)
c.706del p.Asp236IlefsTer9 frameshift_variant Unknown - Simplex 37057675 Schmid CM et al. (2023)
c.978_981del p.Leu326PhefsTer41 frameshift_variant De novo - Simplex 37057675 Schmid CM et al. (2023)
c.982_994dup p.Gly332AlafsTer45 frameshift_variant De novo - Simplex 37057675 Schmid CM et al. (2023)
c.338_351del p.Gln113LeufsTer30 frameshift_variant Unknown - Unknown 37057675 Schmid CM et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

7/1/2023
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.60354106614233

Ranking 362/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.94678968886704

Ranking 2735/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93363340373373

Ranking 12327/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.19694418818648

Ranking 4313/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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