Human Gene Module / Chromosome 20 / NKX2-2

NKX2-2NK2 homeobox 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 2
Rare Variants / Common Variants
0 / 1
Aliases
NKX2-2, NKX2.2,  NKX2B
Associated Syndromes
-
Chromosome Band
20p11.22
Associated Disorders
-
Relevance to Autism

An intergenic SNP adjacent to the NKX2-2 gene (rs910805) reached genome-wide significance (P-value 2.04E-09) in a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) in Grove et al., 2019. A transcriptome-wide association study (TWAS) of 7,805 ASD proband-parent trios, which was subsequently replicated using 35,740 independent samples, using eQTL and splicing quantitative trait loci in 12 brain tissues from GTEx and the CommonMind Consortium (CMC) in Huang et al., 2021 identified NKX2-2 as a gene whose transcriptome-wide association with ASD remained significant after a stringent Bonferroni correction for all genes and all tissues in the analysis (meta-analysis P-value 1.49E-10 in GTEx nucleus accumbens basal ganglia tissue).

Molecular Function

The protein encoded by this gene contains a homeobox domain and may be involved in the morphogenesis of the central nervous system. This gene is found on chromosome 20 near NKX2-4, and these two genes appear to be duplicated on chromosome 14 in the form of TITF1 and NKX2-8. The encoded protein is likely to be a nuclear transcription factor.

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Reports related to NKX2-2 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Identification of common genetic risk variants for autism spectrum disorder Grove J , et al. (2019) Yes -
2 Support - Huang K et al. (2021) Yes -
Rare Variants  

No rare variants reported.

Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 30804558 Grove J , et al. (2019)
SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.57157104506204

Ranking 771/25841 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 0.33733427171404

Ranking 6305/18225 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 0.92917471720752

Ranking 11100/18665 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 -0.38316374707553

Ranking 18188/20870 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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