MBD5 haploinsufficiency due to an intragenic deletion was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2007 (PMID: 17847001). This curation includes heterozygous deletions encompassing all or part of MBD5 and MBD5 truncating variants (PMID: 27786435). Duplications encompassing the entire MBD5 have also been reported in individuals with neurodevelopmental disorders; as these typically also involve other genes and are likely acting via a different molecular mechanism, they are not included in this curation.
Individuals with MBD5 pathogenic variants present with developmental delay, intellectual disability, epilepsy, autism spectrum disorder, severe speech impairment, and behavioral problems (PMIDs: 23422940, 27786435, 33912662). Over 100 individuals with neurodevelopmental disorders and MBD5 LoF variants have been reported in the literature (PMIDs: 17847001, 22495309, 22726846, 23422940, 23708187, 25356899, 27848944, 28807762, 29778030, 30763456, 32193494, 32238909, 33912662), but only 11 probands are included in this curation because the maximum score for genetic evidence has been reached. Most variants are de novo, although inheritance from parents with low level mosaicism has been reported in multiple affected individuals with MBD5 LoF variants (PMIDs: 32238909, 33912662, 36396431). There have also been reports of probands with intragenic MBD5 duplications (PMIDs: 23422940, 33912662), and expression analysis in one patient showed that the encoded aberrant transcripts resulted in premature termination (PMID: 23422940).
The mechanism for disease is predicted to be haploinsufficiency (PMID: 23422940). The gene-disease relationship is also supported by experimental evidence, including a mouse model and a cell culture model (PMID: 25001218).
In summary, there is definitive evidence to support the relationship between MBD5 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 15, 2023 (SOP Version 9). This gene-disease pair was originally evaluated on November 21, 2018 and classified as moderate. Curation of additional genetic evidence resulted in the classification being updated
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