Human Gene Module / Chromosome 6 / MDGA1

MDGA1MAM domain containing glycosylphosphatidylinositol anchor 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
12 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
6p21.2
Associated Disorders
-
Relevance to Autism

Kim et al., 2026 reported two individuals with ASD carrying compound heterozygous missense mutations in the MDGA1 gene [(p.Val116Met/p.Ala688Val) and (p.Tyr635Cys/p.Glu756Gln)]; murine in utero overexpression of MDGA1 p.Val116Met/p.Ala688Val altered cortical neuron migration, while MDGA1 p.Tyr635Cys/p.Glu756Gln disrupted the triangular extracellular structure of MDGA1 and rendered it unable to impact GABAergic synapses in hippocampal CA1 neurons. Furthermore, Kim et al., 2026 found that male Mdga1 knock-in mice harboring the p.Tyr653Cys/p.Glu756Gln mutation exhibited impaired ultrasonic vocalizations and sensorimotor gating, similar to male Mdga1 conditional knockout mice, while no behavioral deficits were seen in female counterparts. Additional de novo and inherited heterozygous variants in the MDGA1 gene were previously identified in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, the SPARK cohort, the MSSNG cohort, and the mAGRE cohort (Lim et al., 2017; Zhou et al., 2022; Fu et al., 2022; Trost et al., 2022; Cirnigliaro et al., 2023). Pettem et al., 2013 demonstrated that MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin.

Molecular Function

This gene encodes a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein that is expressed predominantly in the developing nervous system. In addition to possessing several cell adhesion molecule-like domains, the mature protein has six Ig-like domains, a single fibronectin type III domain, a MAM domain and a C-terminal GPI-anchoring site. Studies in other mammals suggest this protein plays a role in cell adhesion, migration, and axon guidance and, in the developing brain, neuronal migration. In humans, this gene is associated with bipolar disorder and schizophrenia.

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Reports related to MDGA1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development Pettem KL , et al. (2013) No -
2 Support - Perez-Garcia, Carlos G et al. (2016) No -
3 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Fu JM et al. (2022) Yes -
6 Support - Trost B et al. (2022) Yes -
7 Support - Cirnigliaro M et al. (2023) Yes -
8 Primary - Kim, Seungjoon et al. (2026) Yes DD, ID
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2777-7G>T p.? splice_region_variant De novo - - 35982160 Fu JM et al. (2022)
c.1661G>C p.Arg554Pro missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.2668-5C>T p.? splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2254A>C p.Thr752Pro missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.1564T>C p.Phe522Leu missense_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.2280C>G p.Ile760Met missense_variant De novo - Simplex 36368308 Trost B et al. (2022)
c.1586C>T p.Ala529Val missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1904A>G p.Tyr635Cys missense_variant Familial Maternal Simplex 41862769 Kim, Seungjoon et al. (2026)
c.2266G>C p.Glu756Gln missense_variant Familial Paternal Simplex 41862769 Kim, Seungjoon et al. (2026)
c.346G>A p.Val116Met missense_variant Familial Paternal Multiplex 41862769 Kim, Seungjoon et al. (2026)
c.2063C>T p.Ala688Val missense_variant Familial Maternal Multiplex 41862769 Kim, Seungjoon et al. (2026)
c.267_268insGTTC p.Asn90ValfsTer23 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
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.

4/1/2026
3

Initial score established: 3

Krishnan Probability Score

Score 0.49792292931582

Ranking 2315/25841 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 0.99523695671374

Ranking 1509/18225 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 0.94258554296885

Ranking 15362/18665 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 -0.36960060360097

Ranking 18041/20870 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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