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Introduction: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood‐onset RNDs. Methods: In this mixed‐methodology cross‐sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom‐designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. Results: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision‐making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first‐in‐human trials and clinical trial procedures were evident. There was high‐risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. Conclusions: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co‐development and use of educational and psychosocial resources to support clinical decision‐making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. Patient or Public Contribution: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co‐production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources. [ABSTRACT FROM AUTHOR]

Aim: To explore the relationship between social care‐related quality of life (SCrQoL) for caregivers of a child with a developmental and epileptic encephalopathy (DEE; such as SCN2A and Dravet syndrome) and health literacy, illness perceptions, and caregiver activation. Method: As part of a larger pre‐post pilot study of an information linker service, caregivers completed a baseline questionnaire which included demographics and measures to assess SCrQoL, health literacy, illness perceptions, and caregiver activation. We used Spearman's Rho to determine relationships between variables. Results: Seventy‐two caregivers completed the questionnaire. Total SCrQoL varied widely, ranging from an 'ideal state' to 'high needs state'. Caregivers most frequently reported high needs regarding doing activities they enjoy and looking after themselves. Total SCrQoL was correlated with cognitive (r[70] = −0.414, p < 0.000) and emotional representations of illness (r[70] = −0.503, p < 0.000), but not coherence (r = −0.075, p = 0.529). Total SCrQoL was not correlated with health literacy (r[70] = 0.125, p = 0.295) or caregiver activation (r[70] = 0.181, p = 0.127). Interpretation: Future research should explore whether interventions that help caregivers cognitively reframe the negative experiences of having a child with a DEE, and support them to partake in activities they enjoy, boost their SCrQoL. What this paper adds: Caregiver social care‐related quality of life (SCrQoL) varied widely, from 'ideal state' to 'high needs state'.Most common high needs were doing enjoyable activities and self‐care.Caregivers with higher SCrQoL may perceive their child's illness as less threatening.SCrQoL does not appear to be related to caregiver activation in this sample. [ABSTRACT FROM AUTHOR]

Aim: To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs). Method: Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated. Results: Of the 103 patients recruited (54 males, 49 females; aged 2 weeks–17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high‐density chromosomal microarray testing. Interpretation: We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies.KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.Reanalysis of genomic data found the cause in an additional six patients.Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset.Finding the molecular cause led to management changes in 36% of patients with DEEs. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies.KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.Reanalysis of genomic data found the cause in an additional six patients.Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset.Finding the molecular cause led to management changes in 36% of patients with DEEs. [ABSTRACT FROM AUTHOR]

Introduction: Biomedical progress has facilitated breakthrough advanced neurotherapeutic interventions, whose potential to improve outcomes in rare neurological diseases has increased hope among people with lived experiences and their carers. Nevertheless, gene, somatic cell and other advanced neurotherapeutic interventions carry significant risks. Rare disease patient organizations (RDPOs) may enhance patient experiences, inform expectations and promote health literacy. However, their perspectives are understudied in paediatric neurology. If advanced neurotherapeutics is to optimize RDPO contributions, it demands further insights into their roles, interactions and support needs. Methods: We used a mixed‐methodology approach, interviewing 20 RDPO leaders representing paediatric rare neurological diseases and following them up with two online surveys featuring closed and open‐ended questions on advanced neurotherapeutics (19/20) and negative mood states (17/20). Qualitative and quantitative data were analysed using thematic discourse analysis and basic descriptive statistics, respectively. Results: Leaders perceived their roles to be targeted at educational provision (20/20), community preparation for advanced neurotherapeutic clinical trials (19/20), information simplification (19/20) and focused research pursuits (20/20). Although most leaders perceived the benefits of collaboration between stakeholders, some cited challenges around collaborative engagement under the following subthemes: conflicts of interest, competition and logistical difficulties. Regarding neurotherapeutics, RDPO leaders identified support needs centred on information provision, valuing access to clinician experts and highlighting a demand for co‐developed, centralized, high‐level and understandable, resources that may improve information exchange. Leaders perceived a need for psychosocial support within themselves and their communities, proposing that this would facilitate informed decision‐making, reduce associated psychological vulnerabilities and maintain hope throughout neurotherapeutic development. Conclusion: This study provides insights into RDPO research activities, interactions and resource needs. It reveals a demand for collaboration guidelines, central information resources and psychosocial supports that may address unmet needs and assist RDPOs in their advocacy. Patient or Public Contribution: In this study, RDPO leaders were interviewed and surveyed to examine their perspectives and roles in advanced neurotherapeutic development. Some participants sent researchers postinterview clarification emails regarding their responses to questions. [ABSTRACT FROM AUTHOR]

Siblings of young people with chronic illness commonly undertake caring responsibilities for their affected brother/sister, which may encourage maturation, yet may also be perceived as a burden. Our study determined (1) siblings' caring responsibilities, (2) siblings' current emotional distress and psychosocial functioning, and (3) how siblings' caring responsibilities and psychosocial functioning related to familial relationships and coping strategies. Siblings completed questionnaires which contained Sibling Inventory of Behavior, Sibling Inventory of Differential Experiences, PedsQL, emotion thermometers, Brief COPE, and a checklist of caregiving responsibilities. We analyzed the data with t -tests and multi-level models. Forty-five siblings (mean age = 15.40 years, SD = 3.31 years; 60.0% female) participated. Siblings who had caring responsibilities (n = 26, 57.8%) reported lower anxiety symptoms, lower need for help, greater use of problem-focused coping, and more companionship and teaching/directiveness with their affected brother/sister than siblings without caring responsibilities. Siblings reported lower psychosocial and physical functioning when they perceived their parents provided them with less affection than their affected brother/sister. Family-based psychosocial interventions may aim to improve the sibling–parent relationship (including expressing affection) and the sibling–sibling relationship. Future interventions may also focus on increasing siblings' use of problem-focused coping strategies. [ABSTRACT FROM AUTHOR]

Background: The patient voice is becoming increasingly prominent across all stages of therapeutic innovation. It pervades research domains from funding and recruitment, to translation, care, and support. Advances in genomic technologies have facilitated novel breakthrough therapies, whose global developments, regulatory approvals, and confined governmental subsidisations have stimulated renewed hope amongst rare disease patient organisations (RDPOs). With intensifying optimism characterising the therapeutic landscape, researcher-advocate partnerships have reached an inflexion point, at which stakeholders may evaluate their achievements and formulate frameworks for future refinement. Main text: Through this narrative review, we surveyed relevant literature around the roles of RDPOs catering to the rare paediatric neurological disease community. Via available literature, we considered RDPO interactions within seven domains of therapeutic development: research grant funding, industry sponsorship, study recruitment, clinical care and support, patient-reported outcome measures, and research prioritisation. In doing so, we explored practical and ethical challenges, gaps in understanding, and future directions of inquiry. Current literature highlights the increasing significance of ethical and financial challenges to patient advocacy. Biomedical venture philanthropy is gaining momentum amongst RDPOs, whose small grants can incrementally assist laboratories in research, training, and pursuits of more substantial grants. However, RDPO seed funding may encounter long-term sustainability issues and difficulties in selecting appropriate research investments. Further challenges include advocate-industry collaborations, commercial biases, and unresolved controversies regarding orphan drug subsidisation. Beyond their financial interactions, RDPOs serve instrumental roles in project promotion, participant recruitment, biobank creation, and patient registry establishment. They are communication conduits between carers, patients, and other stakeholders, but their contributions may be susceptible to bias and unrealistic expectations. Conclusion: Further insights into how RDPOs navigate practical and ethical challenges in therapeutic development may enhance cooperative efforts. They may also inform resources, whose distribution among advocates, parents, and clinicians, may assist decision-making processes around rare disease clinical trials and treatments. [ABSTRACT FROM AUTHOR]

This is the first of three articles exploring the aspects of clinical care for children with rare neurological disorders including uncertainties old and new. The disruptive technologies of genomic sequencing and advanced therapeutics such as gene-based therapies offer parents of children with severe but rare neurological conditions for the first-time unprecedented opportunities for 'precision medicine'. At the same time, the realities of limited genomic diagnostic yields and not infrequent detection of variants of uncertain significance, lack of natural history study data and management guidelines for individually rare neurogenetic conditions, means that high pre-genomic test expectations are all too often replaced by an accumulation of new uncertainties. This can add to the chronic traumatic stress experienced by many families but may also have under-recognised impacts for their clinicians, contributing to 'burn-out' and attendant negative psychosocial impacts. This first article aims to address how clinicians might manage the accumulation of uncertainties to be more helpful to patients and their families. Moreover, it seeks to address how clinicians can move forward providing compassionate care to their patients and a little more consideration for themselves. [ABSTRACT FROM AUTHOR]

This is the second of a three-part series that explores different aspects of uncertainty, certainty and hope in the context of providing clinical care for children with rare and life-limiting neurological disorders. When caring for families impacted by an overwhelming complex disorder in a child, complicated by threatening uncertainties and potentially more threatening certainties, clinicians utilise skills drawn from differing fields to make the load of information, and the emotional impact more manageable. The first article in this series addressed how clinicians might manage the 'accumulation of uncertainties' and to provide compassionate care not only to their patients, and their families, but also to themselves. This second paper delves into the less helpful aspects of 'certainty', including the associated losses and griefs endured by parents responding to threatening fears associated with their child's condition. In the extreme, disconnection and psychological isolation borne by parents can lead to a sense of hopelessness and desperation. Facing unwelcome certainties - clinicians and parents together - forms the basis of future trust and hope. Clinicians who share the field of trust with families and show commitment to helping parents, even when cure remains elusive, build a sense of hope. This is the sort of hopefulness that clinicians need to have and to offer as they share the journey with families. In this series, we seek to harness a shared approach to face unwelcome certainties and to kindle a sense of hope that is both credible and meaningful to the parents, family and clinician. [ABSTRACT FROM AUTHOR]

Aim: To investigate the psychosocial impact of genetic testing for childhood‐onset developmental and epileptic encephalopathies (DEEs) in order to identify parents' information and support needs. Method: In this mixed‐methods study, we conducted in‐depth semi‐structured interviews with parents (n=25) of children, recruited from the Sydney Children's Hospital Network, Australia, who had received genetic testing. Thematic saturation was reached; interviews were transcribed, deidentified, line‐by‐line coded, and thematically analysed by three coders, using an inductive approach. We also quantitatively assessed the impact of genetic testing on quality of life outcomes and parents' satisfaction with genetics services. Results: Qualitative and quantitative analysis revealed that compassionate genetic counselling and consistent clinician–parent partnerships facilitated parents' capacity to process their child's genetic diagnosis. Parents believed that a sparsity of diagnosis‐specific information to contextualize their child's genetic DEE, combined with limited psychosocial resources to support coping with ongoing prognostic uncertainty, contributed to chronic psychological stress. Access to diagnosis‐specific resources and peer support was considered necessary to support parents in communicating their child's genetic DEE and to reduce social isolation. Interpretation: Integrated psychosocial resources, including tailored psychological supports, diagnosis‐specific information, and peer‐to‐peer supports, are priority areas to complement genetic services. podcast : (https://youtu.be/3tFjqndfQuI) This original article is commented by Tumiene on page 13 of this issue. [ABSTRACT FROM AUTHOR]

This is the third article of a three-part series and addresses how clinicians provide hopefulness meaningfully to families coping with life-limiting and quality of life impairing neurological conditions. The first two articles addressed the enormous challenges faced by carers and also explored the struggles of clinicians trying to provide relief and comfort. Can these families, and those helping clinically, legitimately hope? It is expectation that consolidates desire into a substantial hope that may motivate finding a way forward. Hope must be realistic and directed to something in particular and in someone in particular. Hope and despair are not monolithic but often travel together for both children, families and clinicians. Hope is not denial but a belief that there are positive possibilities. Finding what can be helpfully hoped for and what must be realistically despaired of, is the discerning struggle. Clinicians aim to change what we can and accept what we cannot. Acceptance and grief are arrived at slowly for carers and families. Similarly, clinicians struggle with the hopes of bringing meaningful solace and are supported by trusted colleagues who have shared the same experience. Clinicians strive to respond appropriately and effectively in a dynamic process based on trust, providing presence and compassion when cure is not possible. Clinicians help find the small doable things that foster hope and lessen isolation and abandonment, mindful of the limits of their medical expertise. Surprisingly these modest hopes and faltering acceptances often provide a different form of strength and comfort to sustain a family. [ABSTRACT FROM AUTHOR]

We describe the clinical features of nine unrelated individuals with rare de novo missense or in‐frame deletions/duplications within the "HX motif" of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral‐pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication. [ABSTRACT FROM AUTHOR]

Neurodevelopmental and neurodegenerative disorders (NNDs) are a group of conditions with a broad range of core and co-morbidities, associated with dysfunction of the central nervous system. Improvements in high throughput sequencing have led to the detection of putative risk genetic loci for NNDs, however, quantitative neurogenetic approaches need to be further developed in order to establish causality and underlying molecular genetic mechanisms of pathogenesis. Here, we discuss an approach for prioritizing the contribution of genetic risk loci to complex-NND pathogenesis by estimating the possible impacts of these loci on gene regulation. Furthermore, we highlight the use of a tissue-specificity gene expression index and the application of artificial intelligence (AI) to improve the interpretation of the role of genetic risk elements in NND pathogenesis. Given that NND symptoms are associated with brain dysfunction, risk loci with direct, causative actions would comprise genes with essential functions in neural cells that are highly expressed in the brain. Indeed, NND risk genes implicated in brain dysfunction are disproportionately enriched in the brain compared with other tissues, which we refer to as brain-specific expressed genes. In addition, the tissue-specificity gene expression index can be used as a handle to identify non-brain contexts that are involved in NND pathogenesis. Lastly, we discuss how using an AI approach provides the opportunity to integrate the biological impacts of risk loci to identify those putative combinations of causative relationships through which genetic factors contribute to NND pathogenesis. [ABSTRACT FROM AUTHOR]

The pioneering discovery research of X‐linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide; however, approximately 30% of XLID families still remain unresolved. We postulated that noncoding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene‐regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different noncoding variants. We used comprehensive structural, single‐nucleotide, and repeat expansion analyses of genome sequencing. RNA‐Seq from patient‐derived cell lines, reverse‐transcription polymerase chain reactions, Western blots, and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic noncoding variants: a retrotransposon insertion, a novel intronic splice donor, and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favor of a regulatory noncoding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic noncoding variant discovery. [ABSTRACT FROM AUTHOR]

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis. [ABSTRACT FROM AUTHOR]

Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF , SLC16A2 , and the long non-coding RNA gene FTX. The contribution of the RLIM -flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males. [ABSTRACT FROM AUTHOR]

People with intellectual disability (PWID) consistently identify the importance of health service information that is accessible and relevant. Resources tailored to the information and support needs of PWID can facilitate inclusivity in their health care (including access to genomic medicine) and improve healthcare outcomes. Despite the fact that PWID are commonly referred to genetics services, there is a lack of appropriate resources to help them prepare for their appointments. We therefore aimed to evaluate the feasibility and acceptability of a booklet for PWID to read with their carers prior to their genetics appointment, to help them prepare for what they may experience. With input from Easy to Read experts and PWID who were members of the New South Wales (NSW) Council for Intellectual Disability, the information booklet 'Getting ready for your visit to the genetics clinic' was produced. Australian healthcare professionals (HCP) familiar with clinical genetics services were invited to complete an anonymous online survey designed to assess perceived relevance, readability, and utility of the resource. Recruitment of HCPs was pursued via affiliated clinical services and email distribution through clinical genetics organizations. Sixty‐six HCPs completed and submitted the survey. The results demonstrated that HCPs believed the booklet represented a typical clinical genetics service appointment and that the majority would provide a copy of the resource to clients and their carers. They reported that the booklet was easy to understand and entailed appropriate content and images which were presented clearly and simply. Some minor modifications were recommended and incorporated into the resource. A model of customizable booklets such as this could be transferrable across clinical genetics services and guide development of other resources for PWID. This may help to reduce healthcare disparities, improve client satisfaction, and facilitate involvement of PWID in their own healthcare decisions. [ABSTRACT FROM AUTHOR]

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X. [ABSTRACT FROM AUTHOR]

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE , where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost‐effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways. Methods: We conducted a retrospective cost‐effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well‐phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after “first‐tier” testing. Sensitivity analysis was included with a range of commercial exome and multigene panels. Results: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost‐effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost‐effective. The clinical utility of all diagnoses was reported. Conclusion: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions. [ABSTRACT FROM AUTHOR]

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes. [ABSTRACT FROM AUTHOR]

Background Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum. Methods Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy. Results We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one. Conclusions By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting over 6 million people globally. Although there are symptomatic treatments that can increase the survivability of the disease, there are no curative treatments. The prevalence of PD and disability-adjusted life years continue to increase steadily, leading to a growing burden on patients, their families, society and the economy. Dopaminergic medications can significantly slow down the progression of PD when applied during the early stages. However, these treatments often become less effective with the disease progression. Early diagnosis of PD is crucial for immediate interventions so that the patients can remain self-sufficient for the longest period of time possible. Unfortunately, diagnoses are often late, due to factors such as a global shortage of neurologists skilled in early PD diagnosis. Computer-aided diagnostic (CAD) tools, based on artificial intelligence methods, that can perform automated diagnosis of PD, are gaining attention from healthcare services. In this review, we have identified 63 studies published between January 2011 and July 2021, that proposed deep learning models for an automated diagnosis of PD, using various types of modalities like brain analysis (SPECT, PET, MRI and EEG), and motion symptoms (gait, handwriting, speech and EMG). From these studies, we identify the best performing deep learning model reported for each modality and highlight the current limitations that are hindering the adoption of such CAD tools in healthcare. Finally, we propose new directions to further the studies on deep learning in the automated detection of PD, in the hopes of improving the utility, applicability and impact of such tools to improve early detection of PD globally. [ABSTRACT FROM AUTHOR]

Aim Method Results Interpretation To investigate clinicians' psychosocial experiences navigating interdisciplinary care for children with severe neurological impairment (SNI), for example children with a developmental epileptic encephalopathy; secondarily, to identify preferences for future interventions to support clinicians caring for children with SNI.We conducted a qualitative descriptive study with interdisciplinary clinicians by using a purposeful sampling recruitment strategy. Twenty‐four participants with expertise caring for children with SNI completed in‐depth, semi‐structured interviews. We transcribed the interviews, de‐identified them, and performed inductive thematic analysis.Thematic analysis elicited interrelated themes. Clinicians experienced immense professional barriers providing patient‐centred care across fragmented healthcare contexts. Physical, emotional, and psychological impacts were attributed to inadequate reflective practice training and a paucity of integrated resources to support clinicians over time. Multipronged strategies were prioritized by clinicians, incorporating psychoeducation, interdisciplinary peer mentorship, and psychological resources to build reflective practice skills for clinicians providing complex care in an advancing era of medicine.This study provides novel and in‐depth insight into clinicians' experiences navigating care for children with SNI. The results will be used to inform future integrated and multipronged co‐developed resources tailored for clinicians, on the basis of their recommendations. [ABSTRACT FROM AUTHOR]

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in FMR1 mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55–199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had FMR1 mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features. [ABSTRACT FROM AUTHOR]

Aim: Chromosomal microarray (CMA) is an important diagnostic test for children with multiple congenital anomalies or certain developmental behavioural problems suggestive of an underlying genetic diagnosis. However, there are medical and ethical complexities to its use and few Australian policies to guide practice. We aimed to describe the current practice of Australian paediatricians in relation to CMA testing. We hypothesised that there are knowledge gaps in their use of CMA.Methods: Online survey completed between September 2015 and January 2016 by paediatricians in secondary care settings. Participants were members of the Australian Paediatric Research Network. One hundred and sixty five (43%) of 383 active members responded. Our main outcome measures comprised: (i) the indications for which paediatricians request CMA; (ii) their approach to consent; (iii) their interpretation of results; and (iv) their understanding of the impact on patient management.Results: A significant proportion of paediatricians (21-52%) did not regularly use CMA for conditions with established evidence of diagnostic yield. Paediatricians under-estimated the potential for CMA findings to alter patient management. There was wide variability in paediatricians' approach to consent, and low use of consent forms and fact sheets. Paediatricians reported difficulties interpreting CMA results, with high rates of referral to clinical genetics services.Conclusions: The reported practice of Australian paediatricians is not consistent with international standards on CMA. Australian practice could be improved by a standardised approach to ordering CMA, consenting patients and interpreting results. We provide resources for CMA ordering and make recommendations about preparation for next generation sequencing. [ABSTRACT FROM AUTHOR]

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2 , which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities. [ABSTRACT FROM AUTHOR]