Human Gene Module / Chromosome 11 / MADD

MADDMAP kinase activating death domain

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
10 / 12
Rare Variants / Common Variants
39 / 0
Aliases
-
Associated Syndromes
DEEAH syndrome, Neurodevelopmental disorder with d
Chromosome Band
11p11.2
Associated Disorders
-
Relevance to Autism

Whole-exome sequencing of 115 ASD trios from three countries with a high frequency of consanguineous populations (Pakistan, Iran, and Saudi Arabia) in Harripaul et al., 2026 identified a homozygous missense variant in the MADD gene (NM_001135943.2:c.1883A>G;p.Tyr628Cys) in a male ASD proband from Pakistan. Anazi et al., 2017 had previously reported two unrelated individuals with biallelic MADD variants presenting with developmental delay and poor eye contact; one of these individuals was also reported to have a diagnosis of autism spectrum disorder. Schneeberger et al., 2020 reported that, of the 14 patients with Group 1 MADD-associated disorder (DEEAH syndrome), one presented with autism, while of the nine individuals with Group 2 MADD-associated disorder (neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia), one presented with ASD and another with stereotypic movements. De novo heterozygous missense varants in MADD have been previously reported in ASD probands from the Simons Simplex Collection and the SPARK cohort (Iossifov et al., 2014; Feliciano et al., 2019; Satterstrom et al., 2020; Zhou et al., 2022; Avila et al., 2026), while inherited loss-of-function variants in this gene were observed in multiple individuals with ASD from the iHART and mAGRE cohorts (Ruzzo et al., 2019; Cirnigliaro et al., 2023).

Molecular Function

Tumor necrosis factor alpha (TNF-alpha) is a signaling molecule that interacts with one of two receptors on cells targeted for apoptosis. The apoptotic signal is transduced inside these cells by cytoplasmic adaptor proteins. The protein encoded by this gene is a death domain-containing adaptor protein that interacts with the death domain of TNF-alpha receptor 1 to activate mitogen-activated protein kinase (MAPK) and propagate the apoptotic signal. Biallelic variants in this gene are responsible for two autosomal recessive disorders with some overlapping features: DEEAH syndrome (OMIM 619004), and the less severe neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH; OMIM 619005).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MADD (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No ASD, epilepsy/seizures
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support - Schneeberger, Pauline E et al. (2020) No ASD, stereotypy
7 Support - Zhou X et al. (2022) Yes -
8 Support - Fu JM et al. (2022) Yes -
9 Support - Cirnigliaro M et al. (2023) Yes -
10 Support - Soo-Whee Kim et al. (2024) Yes -
11 Primary - Harripaul, Ricardo et al. (2026) Yes -
12 Support - Natividad Avila, Marina et al. (2026) Yes -
Rare Variants   (39)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
A>G - synonymous_variant De novo - - 35982160 Fu JM et al. (2022)
T>C - missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3390G>A p.Thr1130= synonymous_variant De novo - - 35982160 Fu JM et al. (2022)
C>T - stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1322C>G p.Pro441Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
A>G - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3867A>T p.Leu1289= synonymous_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.4025A>G p.Asp1342Gly missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1540C>T p.Arg514Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.979C>T p.Arg327Ter stop_gained Unknown - Extended multiplex 28940097 Anazi S , et al. (2017)
c.2002G>A p.Ala668Thr missense_variant De novo - Multiplex 31452935 Feliciano P et al. (2019)
c.62_62+3del - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.979C>T p.Arg327Ter stop_gained Unknown - Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.593G>A p.Arg198His missense_variant Unknown - Extended multiplex 28940097 Anazi S , et al. (2017)
c.4594C>T p.Arg1532Ter stop_gained Unknown - Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.1705+1G>C p.? splice_site_variant Unknown - Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.3760-2A>C p.? splice_site_variant Unknown - Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.2930T>G p.Val977Gly missense_variant Familial Both parents Simplex 28940097 Anazi S , et al. (2017)
c.3637_3638delAG p.Ser1213Ter stop_gained Unknown - Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.1061C>T p.Pro354Leu missense_variant Familial - Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.1115C>T p.Pro372Leu missense_variant Familial - Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.3329G>T p.Ser1110Ile missense_variant De novo - Multiplex 41912808 Natividad Avila, Marina et al. (2026)
c.3848A>C p.Tyr1283Ser missense_variant Familial - Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.3637_3638delAG p.Ser1213Ter stop_gained Familial - Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.646C>T p.Arg216Ter stop_gained Familial Both parents Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.979C>T p.Arg327Ter stop_gained Familial Both parents Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.1883A>G p.Tyr628Cys missense_variant Familial Both parents Simplex 41865132 Harripaul, Ricardo et al. (2026)
c.4293G>A p.Trp1431Ter stop_gained Familial Both parents Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.914G>T p.Gly305Val missense_variant Familial Maternal Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.4398delG p.Leu1467CysfsTer20 frameshift_variant Unknown - Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.963+1G>A p.? splice_site_variant Familial Both parents Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.770C>T p.Ser257Phe missense_variant Familial Both parents Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.1037T>C p.Leu346Pro missense_variant Familial Both parents Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.3119T>G p.Leu1040Arg missense_variant Familial Both parents Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.3952T>C p.Trp1318Arg missense_variant Familial Both parents Simplex 32761064 Schneeberger, Pauline E et al. (2020)
c.4080delG p.Lys1361SerfsTer24 frameshift_variant Familial - Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.2834T>C p.Leu945Pro missense_variant Familial Both parents Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.3533_3534delCT p.Ser1178CysfsTer18 frameshift_variant Familial - Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
c.(1862+1_1863-1)_(3759+1_3760-1)del p.? copy_number_loss Familial Paternal Multiplex 32761064 Schneeberger, Pauline E et al. (2020)
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 0.57060752392313

Ranking 898/25841 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 0.0009018234210655

Ranking 11858/18225 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 0.91738990302159

Ranking 8641/18665 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 0.5062410606707

Ranking 483/20870 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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