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.

The International Rett Syndrome Association (IRSA) North American database is the first comprehensive compilation of information in the United States and Canada on individuals with Rett syndrome or with another diagnosis in association with MECP2 mutations. The database contains specific information by diagnosis, mutation status, and mutation type and frequency on 1928 participants. Among the 1928 participants, 85.5% were typical, 13.4% were atypical, and 1.1% had MECP2 mutations but did not have Rett syndrome. MECP2 mutations were identified in 914 of 1059 participants (86%): 799 of 870 (92%) participants with typical Rett syndrome had an MECP2 mutation, 94 of 162 (58%) with atypical Rett syndrome had a mutation, and all 21 individuals diagnosed as Not Rett syndrome had a mutation. Missense-type mutations (39.0%) were slightly more common than nonsense type (35.1%). Individual mutation frequency for the 8 common mutations varied from 11.9% for T158M to 4.4% for R106W; large deletions accounted for 6.4% and C-terminal truncations occurred in 8.8%. The remaining mutations (14.3%) occurred singly or in small numbers. This database provides a unique resource for expanding our understanding of Rett syndrome, for comparison with other national databases, and for future study including organization of clinical trials based on the expected emergence of fundamental therapies.

Individuals with methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS) have varying degrees of severity in their mobility, hand use, developmental skills, and susceptibility to infections. In the present study, we examine the relationship between duplication size, gene content, and overall phenotype in MDS using a clinical severity scale. Other genes typically duplicated within Xq28 (eg, GDI1, RAB39B, FLNA) are associated with distinct clinical features independent of MECP2. We additionally compare the phenotype of this cohort (n = 48) to other reported cohorts with MDS. Utilizing existing indices of clinical severity in Rett syndrome, we found that larger duplication size correlates with higher severity in total clinical severity scores (r = 0.36; P = 0.02), and in total motor behavioral assessment inventory scores (r = 0.31; P = 0.05). Greater severity was associated with having the RAB39B gene duplicated, although most of these participants also had large duplications. Results suggest that developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism are common in MDS. This is the first study to show that duplication size is related to clinical severity. Future studies should examine whether large duplications which do not encompass RAB39B also contribute to clinical severity. Results also suggest the need for creating an MDS specific severity scale.

Objective Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately one in 10,000 female births. The clinical features of RTT are known to impact both patients’ and caretakers’ quality of life (QOL) in RTT. We hypothesized that more severe clinical features would negatively impact caretaker physical QOL but would positively impact caretaker mental QOL. Methods Participants were individuals enrolled in the Rett Natural History Study with a diagnosis of classic RTT. Demographic data, clinical disease features, caretaker QOL, and measures of family function were assessed during clinic visits. The Optum™ SF-36v2® Health Survey was used to assess caretaker physical and mental QOL (higher scores indicate better QOL). Descriptive, univariate, and multivariate analyses were utilized to characterize relationships between child and caretaker characteristics and caretaker QOL. Results Caretaker physical component scores (PCS) were higher than mental component scores (MCS): 52.8 (9.7) versus 44.5 (12.1). No differences were noted between the baseline and 5-year follow-up. In univariate analyses, disease severity was associated with poorer PCS (p=0.006) and improved MCS (p=0.003). Feeding problems were associated with poorer PCS (p=0.007) and poorer MCS (p=0.018). In multivariate analyses, limitations in caretaker personal time and home conflict adversely affected PCS. Feeding problems adversely impacted MCS. Conclusions Caretaker QOL in RTT is similar to that for caretakers in other chronic diseases. Disease characteristics significantly impact QOL, and feeding difficulties may represent an important clinical target for improving both child and caretaker QOL. The stability of QOL scores between baseline and 5-years adds important value.

Objective:The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. Methods:Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. Results:Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. Conclusions:Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures. Rett syndrome (RTT), a neurodevelopmental disorder occurring in 1 of 10,000 female births, 1-5 is characterized by apparently normal psychomotor development during the first 6 -18 months of life followed by regression (loss of purposeful hand use and spoken communication skills), social withdrawal, cognitive impairment, gait dysfunction, 6 and stereotypic hand movements, a hallmark of RTT. 7 Mutations in the methyl-CpG-binding protein 2 gene (MECP2), located at Xq28, account for approximately 95% of individuals with RTT. 8,9 Among the more than 250 different pathogenic mutations, the 8 most common point mutations account for about 60% of individuals with RTT. Small deletions in the C-terminal region of MeCP2 represent an additional 7%-9% and large-scale deletions represent 8%-10%. 10The spectrum of clinical severity for individuals with RTT correlates with specific mutations. Little is known about the impact of RTT on quality of life (QOL). In anticipation of clinical trials, it is essential to understand the applicability of a general QOL measure, particu-