Assessment of 2q23.1 Microdeletion Syndrome Implicates MBD5 as a Single Causal Locus of Intellectual Disability, Epilepsy, and Autism Spectrum Disorder

Abstract

Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders.

A genetic model for neurodevelopmental disease

“…One such example is the 2q23.1 deletion syndrome, which has been associated with intellectual disability, seizures, microcephaly, and speech delay. Recently, the minimal region has been fine mapped via deletions as small as 37 kbp to a single gene-MBD5 [1, [52][53][54][55]. This gene has also been discovered to contain both a rare mutation and common variants as well as translocation breakpoints by sequencing studies of ID, epilepsy, and ASD (Figure 2) [52,53].…”

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

“…4 Further, these NDDs share many overlapping features, including a high prevalence of sleep disturbance. Understanding the molecular alterations in NDDs individually and collectively and the subsequent overlapping pathways affected that lead to the sleep disturbance could possibly lead to behavioral and pharmaceutical therapies.…”

“…4 Genomic disruptions of MBD5 lead to the primary clinical phenotypes present in the disorder, including ID, epilepsy, speech impairment, unusual behaviors, ASD, and broad-based ataxic gate. 4 Sleep disturbance have been previously reported in a few cases.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Interestingly, both NRXN1 and the postsynaptic binding partners NLGN1-4 have been strongly implicated in autism and reviewed elsewhere [106,[167][168][169][170]. MBD5, a methylCpG-binding domain gene, has been identified as the causal gene in the 2q23.1 locus, which is characterized by ASD and ID [171,172]. Deletions encompassing the C-terminus of AUTS2 are associated with autistic features and developmental delay [173].…”