Gene Validity Curation

MBD5 - complex neurodevelopmental disorder

Gene: MBD5 (HGNC:20444)
Classification - 11/21/2018
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism GCEP
Evidence Summary: Variants in MBD5 were first reported in humans with autosomal dominant complex neurodevelopmental disorder as early as 2013 (Carvill et al., 23708187). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 variants have been reported in humans. Variants in this gene have been reported in at least 4 probands in 4 publications (23708187, 25356899, 28807762, 23422940). Variants in this gene segregated with disease in 1 additional family members. The mechanism for disease is haploinsufficiency. Of note, this gene has also been implicated in chromosome 2q23.1 deletion syndrome, which will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/21/18 (SOP Version 6).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 3
5.5
5.5
Carvill GL et al. 2013 Jul (PMID:23708187); Hamdan FF et al. 2014 Oct (PMID:25356899); Bonnet C et al. 2013 Dec (PMID:23422940);
Proband with predicted or proven null variant 1.5 0-2 10 1 1.5 1.5
Han JY et al. 2017 Oct (PMID:28807762);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 7
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Camarena V et al. 2014 Aug (PMID:25001218);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Camarena V et al. 2014 Aug (PMID:25001218);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 7 2.5 9.5 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Moderate
09/26/2019
EXPERT CURATION (DATE)
Moderate
11/21/2018
EVIDENCE SUMMARY
Variants in MBD5 were first reported in humans with autosomal dominant complex neurodevelopmental disorder as early as 2013 (Carvill et al., 23708187). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 variants have been reported in humans. Variants in this gene have been reported in at least 4 probands in 4 publications (23708187, 25356899, 28807762, 23422940). Variants in this gene segregated with disease in 1 additional family members. The mechanism for disease is haploinsufficiency. Of note, this gene has also been implicated in chromosome 2q23.1 deletion syndrome, which will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/21/18 (SOP Version 6).