Human Gene Module / Chromosome 7 / GLI3

GLI3GLI family zinc finger 3

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
9 / 0
Aliases
-
Associated Syndromes
Greig cephalopolysyndactyly syndrome, ASD
Chromosome Band
7p14.1
Associated Disorders
-
Relevance to Autism

A nonsense variant in the GLI3 gene was identified in an individual from the Children's Neurodevelopmental Center, Hasbro Children's Hospital who was diagnosed with ASD and presented with dysmorphic features, sensorineural hearing loss, postaxial polydactyly of the hands and feet, right hydronephrosis, global developmental delay, aggression, self-injurious behavior, sensory processing disorder, anxiety, ADHD, and motor stereotypies (Lob et al., 2024). Siracusano et al., 2019 had previously described a 7-year-old Italian male with Greig cephalopolysyndactyly syndrome and a comorbid diagnosis of autism spectrum disorder who had inherited a frameshift variant in the GLI3 gene from his father, who also had Greig cephalopolysyndactyly syndrome and presented with subclinical autistic symptoms. Two de novo missense variants and a de novo coding-synonymous variant in this gene have also been identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (De Rubeis et al., 2014; Iossifov et al., 2014; Satterstrom et al., 2020).

Molecular Function

This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GLI3 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support - Martina Siracusano et al. (2019) Yes -
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Primary - Karen Lob et al. () Yes ADHD, DD
6 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4408C>T p.Gln1470Ter stop_gained Unknown - - 39136901 Karen Lob et al. ()
c.-54+5del p.? splice_site_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.-54+4A>T p.? splice_region_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.1906G>T p.Ala636Ser missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2993C>A p.Pro998Gln missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.3215A>C p.Asn1072Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.929T>A p.Ile310Lys missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.4428C>T p.Asn1476= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3677del p.Pro1226GlnfsTer4 frameshift_variant Familial Paternal - 31010437 Martina Siracusano et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.46817015559428

Ranking 9032/25841 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 0.9999947394355

Ranking 404/18225 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
Iossifov Probability Score

Score 0.897

Ranking 146/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.73314890869479

Ranking 1400/18665 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 0.013696846143271

Ranking 8253/20870 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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