Global and Local Connectivity Differences Converge With Gene Expression in a Neurodevelopmental Disorder of Known Genetic Origin.

Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioral outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oromotor control difficulties and expressive language impairment. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient across cortical regions in ZDHHC9 mutation cases was significantly associated with known pattern of expression of ZDHHC9 in the normal adult human brain. The results demonstrate that a mutation in a single gene impacts upon white matter organization across the whole-brain, but also shows regionally specific effects, according to variation in gene expression. Furthermore, these regionally specific patterns may link to specific developmental mechanisms, and correspond to specific cognitive deficits

Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study.

BACKGROUND: Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. METHODS: This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. RESULTS: Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function. CONCLUSIONS: Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID.We thank all study participants and their families for extensive contributions to this project. This study was funded by the Academy of Medical Sciences/Wellcome Trust via a Starter Grant for Clinical Lecturers to KB. KB is funded by a National Institute for Health Research Academic Clinical Lectureship. GS is funded by a Wellcome Trust project grant and a James S. McDonnell Foundation Understanding Human Cognition Scholar Award. DEA is funded by an MRC UK intramural programme (MC-A0606-5PQ41). FLR is funded by the National Institute for Health Research (Cambridge Biomedical Research Centre).This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s11689-015-9105-

Childhood intellectual disability and parents' mental health: integrating social, psychological and genetic influences.

BACKGROUND: Intellectual disability has a complex effect on the well-being of affected individuals and their families. Previous research has identified multiple risk and protective factors for parental mental health, including socioeconomic circumstances and child behaviour. AIMS: This study explored whether genetic cause of childhood intellectual disability contributes to parental well-being. METHOD: Children from across the UK with intellectual disability due to diverse genetic causes were recruited to the IMAGINE-ID study. Primary carers completed the Development and Well-being Assessment, including a measure of parental distress (Everyday Feeling Questionnaire). Genetic diagnoses were broadly categorised into aneuploidy, chromosomal rearrangements, copy number variants (CNVs) and single nucleotide variants. RESULTS: Compared with the UK general population, IMAGINE-ID parents (n = 888) reported significantly elevated emotional distress (Cohen's d = 0.546). Within-sample variation was related to recent life events and the perceived impact of children's difficulties. Impact was predicted by child age, physical disability, autistic characteristics and other behavioural difficulties. Genetic diagnosis also predicted impact, indirectly influencing parental well-being. Specifically, CNVs were associated with higher impact, not explained by CNV inheritance, neighbourhood deprivation or family structure. CONCLUSIONS: The mental health of parents caring for a child with intellectual disability is influenced by child and family factors, converging on parental appraisal of impact. We found that genetic aetiologies, broadly categorised, also influence impact and thereby family risks. Recognition of these risk factors could improve access to support for parents, reduce their long-term mental health needs and improve well-being of individuals with intellectual disability.This work was supported by the UK Medical Research Council (grant number G101400 to K.B.), UK Medical Research Council and Medical Research Foundation (grant number MR-N022572-1 to the IMAGINE-ID study; Principle Investigators: David H. Skuse, F Lucy Raymond, Jeremy Hall, Marianne Van den Bree, Michael J. Hall) and the Baily Thomas Charitable Trust (to K.B.)

Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations.

OBJECTIVE: Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss-of-function mutations in ZDHHC9 (OMIM #300799). METHODS: All known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes. RESULTS: Seven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum. INTERPRETATION: Mutations in ZDHHC9 are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter-hemispheric connectivity. The biochemical, cellular and network-level mechanisms responsible for the ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.This study was funded by the Wellcome Trust/Academy of Medical Sciences (Starter Grant for Clinical Lecturers to K. B.). K. B. is funded by the National Institute of Health Research (Academic Clinical Lectureship). J. B. and D. A. are funded by an MRC UK intramural programme (MCA0606- 5PQ41). G. S. is funded by Wellcome Trust project grant (WT079326AIA) and a James S. McDonnell Foundation Understanding Human Cognition Scholar Award. F. L. R. is funded by the National Institute of Health Research (Cambridge Biomedical Research Centre).This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/acn3.196/full

Structural brain abnormalities in a single gene disorder associated with epilepsy, language impairment and intellectual disability.

Childhood speech and language deficits are highly prevalent and are a common feature of neurodevelopmental disorders. However, it is difficult to investigate the underlying causal pathways because many diagnostic groups have a heterogeneous aetiology. Studying disorders with a shared genetic cause and shared cognitive deficits can provide crucial insight into the cellular mechanisms and neural systems that give rise to those impairments. The current study investigated structural brain differences of individuals with mutations in ZDHHC9, which is associated with a specific neurodevelopmental phenotype including prominent speech and language impairments and intellectual disability. We used multiple structural neuroimaging methods to characterise neuroanatomy in this group, and observed bilateral reductions in cortical thickness in areas surrounding the temporo-parietal junction, parietal lobule, and inferior frontal lobe, and decreased microstructural integrity of cortical, subcortical-cortical, and interhemispheric white matter projections. These findings are compared to reports for other genetic groups and genetically heterogeneous disorders with a similar presentation. Overlap in the neuroanatomical phenotype suggests a common pathway that particularly affects the development of temporo-parietal and inferior frontal areas, and their connections

Mental health impact of autism on families of children with intellectual and developmental disabilities of genetic origin

BACKGROUND: Many children with an intellectual or developmental disability (IDD) have associated autism spectrum disorders (ASD), as well as an increased risk of mental health difficulties. In a cohort with IDD of genetic aetiology, we tested the hypothesis that excess risk attached to those with ASD + IDD, in terms of both children's mental health and parental psychological distress. METHODS: Participants with a copy number variant or single nucleotide variant (5–19 years) were recruited via UK National Health Service. 1904 caregivers competed an online assessment of child mental health and reported on their own psychological wellbeing. We used regression to examine the association between IDD with and without co-occurring ASD, and co-occurring mental health difficulties, as well as with parental psychological distress. We adjusted for children's sex, developmental level, physical health, and socio-economic deprivation. RESULTS: Of the 1904 participants with IDD, 701 (36.8%) had co-occurring ASD. Children with both IDD and ASD were at higher risk of associated disorders than those with IDD alone (ADHD: OR = 1.84, 95% confidence interval [CI] 1.46–2.32, p < 0.0001; emotional disorders: OR = 1.85, 95%CI 1.36–2.5, p < 0.0001; disruptive behaviour disorders: OR = 1.79, 95%CI 1.36–2.37, p < 0.0001). The severity of associated symptoms was also greater in those with ASD (hyperactivity: B = 0.25, 95%CI 0.07–0.34, p = 0.006; emotional difficulties: B = 0.91, 95%CI 0.67 to 1.14, p < 0.0001; conduct problems: B = 0.25, 95%CI 0.05 to 0.46, p = 0.013). Parents of children with IDD and ASD also reported greater psychological distress than those with IDD alone (β = 0.1, 95% CI 0.85 to 2.21, p < 0.0001). Specifically, in those with ASD, symptoms of hyperactivity (β = 0.13, 95% CI 0.29–0.63, p < 0.0001), emotional difficulties (β = 0.15, 95% CI 0.26–0.51, p < 0.0001) and conduct difficulties (β = 0.07, 95% CI 0.07–0.37, p < 0.004) all significantly contributed to parental psychological distress. CONCLUSIONS: Among children with IDD of genetic aetiology, one third have co-occurring ASD. Not only do those with co-occurring ASD present with a wider range of associated mental health disorders and more severe mental health difficulties than those with IDD alone, but their parents also experience more psychological distress. Our findings suggest that the additional mental health and behavioural symptoms in those with ASD contributed to the degree of parental psychological distress

Recommendations for designing genetic test reports to be understood by patients and non-specialists.

Funder: David and Claudia Harding FoundationPatients and non-specialist healthcare professionals are increasingly expected to understand and interpret the results of genetic or genomic testing. These results are currently reported using a variety of templates, containing different amounts, levels, and layouts of information. We set out to establish a set of recommendations for communicating genetic test results to non-expert readers. We employed a qualitative-descriptive study design with user-centred design principles, including a mixture of in-person semi-structured interviews and online questionnaires with patients, healthcare professionals and the general public. The resulting recommendations and example template include providing at-a-glance comprehension of what the test results mean for the patient; suggested next steps; and details of further information and support. Separation and inclusion of technical methodological details enhances non-specialists' understanding, while retaining important information for specialists and the patients' records. The recommendations address the high-level needs of patients and their non-specialist clinicians when receiving genetic test results. These recommendations provide a solid foundation for the major content and structure of reports, and we recommend further engagement with patients and clinicians to tailor reports to specific types of test and results

Mapping the Constrained Coding Regions in the human genome to their corresponding proteins

Constrained Coding Regions (CCRs) in the human genome have been derived from DNA sequencing data of large cohorts of healthy control populations, available in the Genome Aggregation Database (gnomAD) [1]. They identify regions depleted of protein-changing variants and thus identify segments of the genome that have been constrained during human evolution. By mapping these DNA-defined regions from genomic coordinates onto the corresponding protein positions and combining this information with protein annotations, we have explored the distribution of CCRs and compared their co-occurrence with different protein functional features, previously annotated at the amino acid level in public databases. As expected, our results reveal that functional amino acids involved in interactions with DNA/RNA, protein-protein contacts and catalytic sites are the protein features most likely to be highly constrained for variation in the control population. More surprisingly, we also found that linear motifs, linear interacting peptides (LIPs), disorder-order transitions upon binding with other protein partners and liquid-liquid phase separating (LLPS) regions are also strongly associated with high constraint for variability. We also compared intra-species constraints in the human CCRs with inter-species conservation and functional residues to explore how such CCRs may contribute to the analysis of protein variants. As has been previously observed, CCRs are only weakly correlated with conservation, suggesting that intraspecies constraints complement interspecies conservation and can provide more information to interpret variant effects

Rare Genetic Variation in 135 Families With Family History Suggestive of X-Linked Intellectual Disability.

Families with multiple male children with intellectual disability (ID) are usually suspected of having disease due to a X-linked mode of inheritance and genetic studies focus on analysis of segregating variants in X-linked genes. However, the genetic cause of ID remains elusive in approximately 50% of affected individuals. Here, we report the analysis of next-generation sequencing data in 274 affected individuals from 135 families with a family history suggestive of X-linked ID. Genetic diagnoses were obtained for 19% (25/135) of the families, and 24% (33/135) had a variant of uncertain significance. In 12% of cases (16/135), the variants were not shared within the family, suggesting genetic heterogeneity and phenocopies are frequent. Of all the families with reportable variants (43%, 58/135), we observed that 55% (32/58) were in X-linked genes, but 38% (22/58) were in autosomal genes, while the remaining 7% (4/58) had multiple variants in genes with different modes on inheritance. This study highlights that in families with multiple affected males, X linkage should not be assumed, and both individuals should be considered, as different genetic etiologies are common in apparent familial cases

Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability.

Mutations in the HECT, UBA and WWE domain-containing 1 (HUWE1) E3 ubiquitin ligase cause neurodevelopmental disorder X-linked intellectual disability (XLID). HUWE1 regulates essential processes such as genome integrity maintenance. Alterations in the genome integrity and accumulation of mutations have been tightly associated with the onset of neurodevelopmental disorders. Though HUWE1 mutations are clearly implicated in XLID and HUWE1 regulatory functions well explored, currently much is unknown about the molecular basis of HUWE1-promoted XLID. Here we showed that the HUWE1 expression is altered and mutation frequency increased in three different XLID individual (HUWE1 p.R2981H, p.R4187C and HUWE1 duplication) cell lines. The effect was most prominent in HUWE1 p.R4187C XLID cells and was accompanied with decreased DNA repair capacity and hypersensitivity to oxidative stress. Analysis of HUWE1 substrates revealed XLID-specific down-regulation of oxidative stress response DNA polymerase (Pol) λ caused by hyperactive HUWE1 p.R4187C. The subsequent restoration of Polλ levels counteracted the oxidative hypersensitivity. The observed alterations in the genome integrity maintenance may be particularly relevant in the cortical progenitor zones of human brain, as suggested by HUWE1 immunofluorescence analysis of cerebral organoids. These results provide evidence that impairments of the fundamental cellular processes, like genome integrity maintenance, characterize HUWE1-promoted XLID