Relevance to Autism

MBD5 was originally identified as a candidate gene in a report describing copy number variation in patients with unexplained mental retardation (Wagenstaller et al., 2007). Since that report, numerous studies have implicated MBD5 haploinsufficiency as being associated with intellectual disability, epilepsy, and autism spectrum disorder (Jaillard et al., 2009; van Bon et al., 2010; Williams et al., 2010; Talkowski et al., 2011). In particular, Talkowski et al. (2011) showed that the MBD5 locus defines the critical region of 2q23.1 microdeletion syndrome and showed significant reduction in MBD5 RNA expression in lymphoblastoid cell lines of individuals with MBD5 deletions. That report also showed association of a missense variant (Gly79Glu) in 6/747 ASD cases compared to 3/3042 controls (P=0.012). More recently, a balanced chromosomal abnormality (BCA) leading to MBD5 disruption was identified in an ASD case (Talkowski et al., 2012). Mullegama et al., 2014 demonstrated that 2q23.1 microduplications affecting the MBD5 gene resulted in a duplication syndrome complementary to the 2q23.1 microdeletion syndrome . De novo likely gene-disruptive/protein-truncating variants in the MBD5 gene have been identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (O'Roak et al., 2012; Lim et al., 2017). TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified MBD5 as a candidate gene with a false discovery rate (FDR) 0.01. A de novo loss-of-function variant and several missense variants in the MBD5 gene were reported in ASD proband from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified MBD5 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a member of the methyl-CpG-binding domain (MBD) family. Mutations in this gene cause mental retardation autosomal dominant type 1. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures.

External Links

References