Intellectual disability syndromic and non-syndromic
Gene: MADD

MADD (MAP kinase activating death domain)
EnsemblGeneIds (GRCh38): ENSG00000110514
EnsemblGeneIds (GRCh37): ENSG00000110514
OMIM: 603584, Gene2Phenotype
MADD is in 6 panels

3 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

OMIM have assigned two disease entities to this gene.

DEEAH syndrome: 12 families.
NEDDISH syndrome: 8 families.
Created: 20 Sep 2020, 10:28 p.m. | Last Modified: 20 Sep 2020, 10:28 p.m.

Panel Version: 0.3019

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities); Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005

Publications

Created: 20 Sep 2020, 10:28 p.m.
Last Modified: 20 Sep 2020, 10:28 p.m.
Panel version: 0.3019

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, 12:44 p.m. | Last Modified: 9 Aug 2020, 12:44 p.m.

Panel Version: 0.2835

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, 12:44 p.m.
Last Modified: 9 Aug 2020, 12:44 p.m.
Panel version: 0.2835

Sue White (Victorian Clinical Genetics Services)

Green List (high evidence)

Gene is red in PanelAppUK but 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: 29 Jan 2020, 2:18 a.m. | Last Modified: 29 Jan 2020, 2:18 a.m.

Panel Version: 0.1756

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
intellectual disability

Publications

28940097

Created: 29 Jan 2020, 2:18 a.m.
Last Modified: 29 Jan 2020, 2:18 a.m.
Panel version: 0.1756

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
Genetic Health Queensland

Phenotypes

DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities)
Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005

OMIM

603584

Clinvar variants

Variants in MADD

Penetrance

None

Publications

Panels with this gene