Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities

Abstract

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 contribute to a spectrum of neurodevelopmental phenotypes, however the impact of this locus in human psychopathology has not been described. To characterize the structural variation landscape of MBD5 disruptions and the associated psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation, and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5′UTR, confirming the critical impact of non-coding sequence at this locus. We found heterogeneous, multi-system pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, which includes sensory integration disorder, anxiety, self-hugging, bipolar disorder and others. Importantly, unique features of the oldest assessed patient were early-onset dementia and behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study indicates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology, and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also suggests that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression and early-onset dementia.

Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND)

“…Motor delays with poor coordination and broad-based/ataxic gait are seen in over 70% of individuals, 2,5,6 with the average age of walking 2-3 years of age. 2,6 Language development is severely impaired in individuals with 2q23.1 deletion syndrome.…”

“…Motor delays with poor coordination and broad-based/ataxic gait are seen in over 70% of individuals, 2,5,6 with the average age of walking 2-3 years of age. 2,6 Language development is severely impaired in individuals with 2q23.1 deletion syndrome. Most reported pediatric cases either lack speech entirely 2 or have single words (2-3 word phrases), 5,7 and a few individuals speak 2-6 sentences.…”

“…Most reported pediatric cases either lack speech entirely 2 or have single words (2-3 word phrases), 5,7 and a few individuals speak 2-6 sentences. 5,6 Because of the limited speech and the broad-based ataxic gait, Angelman syndrome (AS) (MIM #105830) was considered in the diagnostic differential for some individuals who were eventually diagnosed with 2q23.1 deletions. 5 …”

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

“…These sleep studies further support previous reports regarding del 2q23.1 patients' sleep habits. [4][5][6][7][8][9][10][11][12] Although this survey may reflect a subjective measure of the sleep phenotype present in 2q23.1 deletion syndrome patients as parents/guardians answered the survey, parents are in a unique position to describe their child's regular sleep behaviors. Importantly,~55.6% of parents reported that they use medication to improve the poor sleep patterns in their children, which is a significant indicator of the difficulties faced by the child and the family because of the sleep problems.…”

“…4 Sleep disturbance have been previously reported in a few cases. [4][5][6][7][8][9][10][11][12] Some of the sleep disturbances mentioned in these cases are waking 6-8 times per night, apparent night terrors in the early part of sleep, and waking in the early hours of the morning. [4][5][6][7][8][9][10][11][12] Although it is clear a sleep disturbance exists in del 2q23.1, no systematic characterization of the extent of sleep problems in this population has been published.…”