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Intellectual disability

Gene: MADD

Green List (high evidence)
MADD (MAP kinase activating death domain)
EnsemblGeneIds (GRCh38): ENSG00000110514
EnsemblGeneIds (GRCh37): ENSG00000110514
OMIM: 603584, Gene2Phenotype
MADD is in 3 panels

4 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Comments from Karen Stals (Royal Devon and Exeter Hospital), 4 Dec 2023: Apnoea a presenting feature in 13/14 patients with MADD-related disorder with biallelic MADD variants in Schneeberger et al 2020 PMID: 32761064. Identified biallelic variants in this gene in a patient with a consistent phenotype.
Created: 6 Feb 2024, 1:16 p.m. | Last Modified: 6 Feb 2024, 1:16 p.m.
Panel Version: 5.442
The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510

Publications

Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 5.442

Ivone Leong (Genomics England Curator)

Comment on list classification: Based on expert review provided by Konstantinos Varvagiannis and Zornitza Stark, there is enough evidence to support a gene-disease association. This gene has been promoted from Red to Amber and will be promoted to Green status at next panel review.
Created: 8 Oct 2020, 2:04 p.m. | Last Modified: 8 Oct 2020, 2:04 p.m.
Panel Version: 3.393
Created: 8 Oct 2020, 2:04 p.m.
Last Modified: 8 Oct 2020, 2:04 p.m.
Panel version: 3.393

Konstantinos Varvagiannis (Other)

Green List (high evidence)

There are 3 reports on the phenotype of individuals with biallelic pathogenic MADD variants. Clinical presentation appears to be relevant for inclusion of this gene in both ID and epilepsy panels. A recent study provides extensive clinical details and suggests that the phenotype may range from DD/ID to a severe pleiotropic disorder characterized by severe DD (and ID), sensory and autonomic dysfunction, exocrine and endocrine insufficiency and haematological anomalies). Seizures have been reported in several individuals with either presentation.
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Anazi et al (2017 - PMID: 28940097) identified MADD as a potential ID gene. The authors described a girl with profound DD and seizures among other features. The child, deceased at the age of 14m, was born to consanguineous Saoudi parents and was found to harbour a homozygous missense SNV [NM_003682.3:c.2930T>G:p.(Val977Gly)]. Through GeneMatcher, the authors identified a further 6 y.o. girl, compound heterozygous for a missense and a stopgain variant [NM_003682.3:c.593G>A:p.(Arg198His) and c.979C>T:p.(Arg327*)]. The child had normal development and milestones until the age of 15m, when she demonstrated delay in speech, social interactions, poor eye contact and was later diagnosed with ASD.
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Hu et al (2019 - PMID: 29302074) provided details on a 22- and 30- y.o. female born to (reportedly) unrelated parents. Formal evaluation (WAIS-IV) suggested ID in the mild to moderate range(IQs of 50 and 60 respectively). Both were homozygous for an indel [NM_003682:c.3559del / p.(Met1187*)].
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Schneeberger et al (2020 - PMID: 32761064) report on 23 affected subjects.

The authors categorized the phenotypes in 2 groups. 9 individuals belonging to group 1 presented with hypotonia, DD (9/9) with speech impaiment, ID (5/5) and seizures (6/9). 14 patients, belonging to group 2 had DD (9/9 - severe), ID (3/3), seizures (9/14), endo- and exocrine dysfunction, impairment of sensory and autonomic nervous system, haematological anomalies. The course was fatal in some cases, within the later group. Some facial features appeared to be more frequent (e.g. full cheeks, small mouth, tented upper lip - small palpebral fissures in some, etc). Genital anomalies were also common in males from both groups.

All were found to harbor biallelic MADD variants (21 different - missense and pLoF SNVs as well as an intragenic deletion). Variants in all cases affected all 7 isoforms. Data did not allow genotype-phenotype correlations e.g. individuals with missense and a pLoF variant (in trans) were identified within either group.

Studies using patient-derived fibroblasts supported the role of the variants, e.g. lower mRNA levels for those where NMD would apply, deficiency or drastic reduction of the protein upon immunobloting (also the case for missense variants) and mRNA analyses demonstrating aberrant transcripts for 2 relevant variants.

MADD encodes the MAPK-activating protein containing a death domain implicated among others in neurotransmission (Rab3 GEF and effector playing a role in formation/trafficking of synaptic vessicles), cell survival (pro-apoptotic effects/protection against apoptosis upon TNF-a treatment), etc. The gene has relevant expression pattern in fetal and adult brain (discussed by Hu et al).

Studies in patient fibroblasts provide evidence of reduced activation of MAP kinases ERK1/2 upon treatment with TNF-a, activation of the intrinsic (TNF-a-dependent-) apoptosis. MADD deficiency was shown to result to decreased EGF endocytosis (likely mediated by Rab3).

Mouse model further supports the role of MADD (summary by MGI: "Mice homozygous for a knock-out allele die shortly after birth due to respiratory failure, are hyporesponsive to tactile stimuli, and exhibit defects in neurotransmitter release with impaired synaptic vesicle trafficking and depletion of synaptic vesicles at the neuromuscular junction.").

You may consider inclusion in other gene panels e.g. for hematologic (low Hb and thrombocytopenia in several) or GI (e.g diarrhea) disorders.
Created: 9 Aug 2020, 12:47 p.m. | Last Modified: 9 Aug 2020, 12:47 p.m.
Panel Version: 3.239

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay / Intellectual disability / Seizures; Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system

Publications

Created: 9 Aug 2020, 12:47 p.m.
Last Modified: 9 Aug 2020, 12:47 p.m.
Panel version: 3.239

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Anazi et al report 2 unrelated families with ID and biallelic variants. No specific functional data for variants but MADD is a regulator of neurotransmitter release and mouse model exhibits severe neuronal defects with early lethality (Del Villar and Miller 2004; Tanaka et al. 2001)
Created: 6 Mar 2020, 10 a.m. | Last Modified: 6 Mar 2020, 10 a.m.
Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 6 Mar 2020, 10 a.m.
Last Modified: 6 Mar 2020, 10 a.m.
Panel version: 3.3

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • DEEAH syndrome, OMIM:619004
  • deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005
  • neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562
OMIM
603584
Clinvar variants
Variants in MADD
Penetrance
None
Publications
Panels with this gene

History Filter Activity

12 Feb 2024, Gel status: 3

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562

9 Mar 2022, Gel status: 3

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: MADD was changed from to BIALLELIC, autosomal or pseudoautosomal

9 Mar 2022, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review was removed from gene: MADD.

9 Mar 2022, Gel status: 3

Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Green was added to MADD. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

8 Oct 2020, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag for-review tag was added to gene: MADD.

8 Oct 2020, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: madd has been classified as Amber List (Moderate Evidence).

8 Oct 2020, Gel status: 1

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: MADD were set to

8 Oct 2020, Gel status: 1

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: MADD were changed from to Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004

29 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: MADD was added gene: MADD was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: MADD was set to