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A case of a missense RBM10 variant in an adult with mild to moderate intellectual disability. Now, with two reported cases, distinct phenotypic traits unique to I RBM10 i missense variants, in addition to intellectual disability, remain to be clarified. [Extracted from the article]

Abstract: Background: Pallister‐Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. Methods: We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. Results: We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region‐specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. Conclusion: Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder. [ABSTRACT FROM AUTHOR]

Background: Advances in screening and diagnostics have changed the way in which we identify and diagnose congenital anomalies. Objective: To examine changes in rates of prenatal diagnosis of congenital anomalies over time and by demographic characteristics. Methods: We undertook a population‐based retrospective cohort study of all children born in Western Australia between 1980 and 2020 and diagnosed with a congenital anomaly. Age at diagnosis (prenatal, neonatal, infancy, early childhood or childhood) prevalence (all‐type and type‐specific), and prevalence ratios (PR) were calculated. We fit joinpoint regression models to describe the average annual percentage change (APC) in prenatal diagnosis over time, and log‐binomial regression models to estimate the association between prenatal diagnosis and demographic characteristics. Results: Prenatal diagnosis prevalence between the first (1980–1989: 28.3 per 10,000 births) and last (2005–2014: 156.1 per 10,000 births) decades of the study increased 5.5‐fold (95% confidence interval [CI] 5.0, 5.9). Substantial increases were observed for cardiovascular (PR 10.7, 95% CI 8.0, 14.6), urogenital (PR 10.5, 95% CI: 8.7, 12.6) and chromosomal anomalies (PR 7.0, 95% CI 5.9, 8.3). Prenatal diagnosis was positively associated with the birth year (adjusted risk ratio [RR] 1.04, 95% CI 1.03, 1.04), advanced maternal age (RR 1.14, 95% CI 1.11, 1.18), multiple anomalies (RR 2.86, 95% CI 2.77, 2.96) and major anomalies (RR 3.75, 95% CI 3.36, 4.19), and inversely associated with remoteness (RR 0.89, 95% CI: 0.83, 0.95) and Aboriginality (RR 0.90, 95% CI 0.83, 0.97). Conclusions: Increases in prenatal diagnosis of congenital anomalies were observed in Western Australia from 1980 to 2020, reflecting advances in screening. Prenatal diagnosis was less common in remote regions and in Aboriginal children, strengthening calls for increased provision of antenatal care services for these populations. [ABSTRACT FROM AUTHOR]

Background: New approaches are required to address the needs of complex undiagnosed diseases patients. These approaches include clinical genomic diagnostic pipelines, utilizing intra- and multi-disciplinary platforms, as well as specialty-specific genomic clinics. Both are advancing diagnostic rates. However, complementary cross-disciplinary approaches are also critical to address those patients with multisystem disorders who traverse the bounds of multiple specialties and remain undiagnosed despite existing intra-specialty and genomic-focused approaches. The diagnostic possibilities of undiagnosed diseases include genetic and non-genetic conditions. The focus on genetic diseases addresses some of these disorders, however a cross-disciplinary approach is needed that also simultaneously addresses other disorder types. Herein, we describe the initiation and summary outcomes of a public health system approach for complex undiagnosed patients - the Undiagnosed Diseases Program-Western Australia (UDP-WA).Results: Briefly the UDP-WA is: i) one of a complementary suite of approaches that is being delivered within health service, and with community engagement, to address the needs of those with severe undiagnosed diseases; ii) delivered within a public health system to support equitable access to health care, including for those from remote and regional areas; iii) providing diagnoses and improved patient care; iv) delivering a platform for in-service and real time genomic and phenomic education for clinicians that traverses a diverse range of specialties; v) retaining and recapturing clinical expertise; vi) supporting the education of junior and more senior medical staff; vii) designed to integrate with clinical translational research; and viii) is supporting greater connectedness for patients, families and medical staff.Conclusion: The UDP-WA has been initiated in the public health system to complement existing clinical genomic approaches; it has been targeted to those with a specific diagnostic need, and initiated by redirecting existing clinical and financial resources. The UDP-WA supports the provision of equitable and sustainable diagnostics and simultaneously supports capacity building in clinical care and translational research, for those with undiagnosed, typically rare, conditions. [ABSTRACT FROM AUTHOR]

Background: The Rare and Undiagnosed Diseases Diagnostic Service (RUDDS) refers to a genomic diagnostic platform operating within the Western Australian Government clinical services delivered through Genetic Services of Western Australia (GSWA). GSWA has provided a state-wide service for clinical genetic care for 28 years and it serves a population of 2.5 million people across a geographical area of 2.5milion Km(2). Within this context, GSWA has established a clinically integrated genomic diagnostic platform in partnership with other public health system managers and service providers, including but not limited to the Office of Population Health Genomics, Diagnostic Genomics (PathWest Laboratories) and with executive level support from the Department of Health. Herein we describe report presents the components of this service that are most relevant to the heterogeneity of paediatric clinical genetic care.Results: Briefly the platform : i) offers multiple options including non-genetic testing; monogenic and genomic (targeted in silico filtered and whole exome) analysis; and matchmaking; ii) is delivered in a patient-centric manner that is resonant with the patient journey, it has multiple points for entry, exit and re-entry to allow people access to information they can use, when they want to receive it; iii) is synchronous with precision phenotyping methods; iv) captures new knowledge, including multiple expert review; v) is integrated with current translational genomic research activities and best practice; and vi) is designed for flexibility for interactive generation of, and integration with, clinical research for diagnostics, community engagement, policy and models of care.Conclusion: The RUDDS has been established as part of routine clinical genetic services and is thus sustainable, equitably managed and seeks to translate new knowledge into efficient diagnostics and improved health for the whole community. [ABSTRACT FROM AUTHOR]

There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term 'phenotype' is usually taken to mean some deviation from normal morphology, physiology and behaviour. It is ascertained via history, examination and investigations, and a primary aim is diagnosis. Therefore, doctors are, by necessity, expert 'phenotypers'. There is an inherent and partially realised power in phenotypic information that when harnessed can improve patient care. Furthermore, phenotyping developments are increasingly important in an era of rapid advances in genomic technology. Fortunately, there is an expanding network of phenotyping tools that are poised for clinical translation. These tools will preferentially be implemented to mirror clinical workflows and to integrate with advances in genomic and information-sharing technologies. This will synergise with and augment the clinical acumen of medical practitioners. We outline key enablers of the ascertainment, integration and interrogation of clinical phenotype by using genetic diseases, particularly rare ones, as a theme. Successes from the test bed or rare diseases will support approaches to common disease. [ABSTRACT FROM AUTHOR]

With advances in therapeutics for rare, genetic and syndromic diseases, there is an increasing need for objective assessments of phenotypic endpoints. These assessments will preferentially be high precision, non-invasive, non-irradiating, and relatively inexpensive and portable. We report a case of a child with an extensive lymphatic vascular malformation of the head and neck, treated with an mammalian target of Rapamycin (mTOR) inhibitor that was assessed using 3D facial analysis. This case illustrates that this technology is prospectively a cost-effective modality for treatment monitoring, and it supports that it may also be used for novel explorations of disease biology for conditions associated with disturbances in the mTOR, and interrelated, pathways. [ABSTRACT FROM AUTHOR]

For decades the relationships of twinning and alterations in body patterning, such as laterality and asymmetry, have been investigated. However, the tools to define and quantify these relationships have been limited and the majority of these studies have relied on associations with subjectively defined phenotypes. The emerging technologies of 3-dimensional (3D) facial scanning and geometric morphometrics are providing the means to establish objective criteria, including measures of asymmetry, which can be used for phenotypic classification and investigations. Additionally, advances in molecular epigenetics provide new opportunities for novel investigations of mechanisms central to early developmental processes, twinning and related phenotypes. We review the evidence for overlapping etiologies of twinning, asymmetry and selected monogenic and complex diseases, and we suggest that the combination of epigenetic investigations with detailed and objective phenotyping, utilizing 3D facial analysis tools, can reveal insights into the genesis of these phenomena. [ABSTRACT FROM AUTHOR]

We report on a 3-year-old girl, from a 3-generation family with an FGFR3 Pro250Arg mutation, who in addition to craniosynostosis, had a laterality disorder and hepatoblastoma, following a pregnancy complicated by maternal insulin-dependent diabetes. The clinical features possibly result from the combined effects of the maternal diabetes and the familial FGFR3 mutation, thus representing a unique gene-environment interaction that may have implications for the understanding of the phenotypes described in this child. [ABSTRACT FROM AUTHOR]

Abstract: Cytokine gene polymorphisms affect vaccine responses and gender-specific effects are known for many phenotypes. Therefore, this study investigated gender-specific effects of cytokine gene polymorphisms on vaccine responses. In 263 2-year-old subjects selected for parental history of atopy, boys with IL-4 C-589T and IL-4Rα I50V genotypes associated with atopy had increased Diptheria Toxoid (DiphTox) and Tetanus Toxoid (TetTox) responses compared with the remaining alleles (IL-4 C-589T: DipTox p =0.01, TetTox p =0.04; IL-4Rα.I50V: DipTox p =0.04, TetTox p =0.08). Contrastingly, girls with IL-10 -592C genotypes associated with atopy had lower levels of DiphTox (p =0.03) and TetTox (p =0.02) responses compared with the remaining allele. Additionally, interaction effects were found for IL-4 C-589T (p =0.01) and IL-4Rα I50V (p =0.04) polymorphisms. In conclusion, these findings support the interaction of primary genetic and modifying factors on vaccine responses and the importance of atopic genetics to these responses. [Copyright &y& Elsevier]

Abstract: Background: Significant differences in immune responses upon vaccination have been described, suggesting genetics are important in determining the magnitude of vaccine responses. The interleukin (IL)-4 pathway, including IL-4, IL-13 and the IL-4 receptor α chain (IL-4 Rα), is central to humoral responses and therefore could have an impact on vaccine responsiveness. Objective: To investigate whether single nucleotide polymorphisms (SNPs) in the IL-4, IL-13 and IL-4 RA genes influence pneumococcal serotype-specific IgG antibody responses. Methods: SNPs in the IL-4 gene (C −589T, G2979T), the IL-13 gene (G −1112A, Arg130Gln) and in the IL-4 RA gene (Ile50Val, Gln551Arg) were investigated in isolation and in combination, for their influence on serotype-specific IgG antibody responses upon combined pneumococcal conjugate and polysaccharide vaccinations in children with a history of recurrent otitis media. Results: Lower antibody responses were observed for alleles previously associated with atopy, IL-4 −589T, IL-4 2979T and IL-4 Rα 551Gln. Effects were stronger in gene haplotype combinations or in multiple haplotype combination analyses. Conclusion: This study highlights the importance of host genetic factors in vaccine responses. Furthermore, it supports the approach of studying the effect of combinations of multiple alleles, in haplotypes or in combinations of haplotypes, on complex phenotypes within a biological pathway. [Copyright &y& Elsevier]

MECP2 duplication syndrome (MDS) is a rare, X-linked, neurodevelopmental disorder caused by a duplication of the methyl-CpG-binding protein 2 (MECP2) gene-a gene in which loss-of-function mutations lead to Rett syndrome (RTT). MDS has an estimated live birth prevalence in males of 1/150,000. The key features of MDS include intellectual disability, developmental delay, hypotonia, seizures, recurrent respiratory infections, gastrointestinal problems, behavioural features of autism and dysmorphic features-although these comorbidities are not yet understood with sufficient granularity. This review has covered the past two decades of MDS case studies and series since the discovery of the disorder in 1999. After comprehensively reviewing the reported characteristics, this review has identified areas of limited knowledge that we recommend may be addressed by better phenotyping this disorder through an international data collection. This endeavour would also serve to delineate the clinical overlap between MDS and RTT. [ABSTRACT FROM AUTHOR]

Monogenic rare disorders contribute significantly to paediatric morbidity and mortality, and elucidation of the underlying genetic cause may have benefits for patients, families and clinicians. Advances in genomic technology have enabled diagnostic yields of up to 50% in some paediatric cohorts. This has led to an increase in the uptake of genetic testing across paediatric disciplines. This can place an increased burden on paediatricians, who may now be responsible for interpreting and explaining test results to patients. However, genomic results can be complex, and sometimes inconclusive for the ordering paediatrician. Results may also cause uncertainty and anxiety for patients and their families. The paediatrician's genetic literacy and knowledge of genetic principles are therefore critical to inform discussions with families and guide ongoing patient care. Here, we present four hypothetical case vignettes where genomic testing is undertaken, and discuss possible results and their implications for paediatricians and families. We also provide a list of key terms for paediatricians. [ABSTRACT FROM AUTHOR]

Rare genetic diseases affect 5–8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations. [ABSTRACT FROM AUTHOR]

Objective: Clinical deep phenotyping and phenotype annotation play a critical role in both the diagnosis of patients with rare disorders as well as in building computationally-tractable knowledge in the rare disorders field. These processes rely on using ontology concepts, often from the Human Phenotype Ontology, in conjunction with a phenotype concept recognition task (supported usually by machine learning methods) to curate patient profiles or existing scientific literature. With the significant shift in the use of large language models (LLMs) for most NLP tasks, we examine the performance of the latest Generative Pre-trained Transformer (GPT) models underpinning ChatGPT as a foundation for the tasks of clinical phenotyping and phenotype annotation. Materials and methods: The experimental setup of the study included seven prompts of various levels of specificity, two GPT models (gpt-3.5-turbo and gpt-4.0) and two established gold standard corpora for phenotype recognition, one consisting of publication abstracts and the other clinical observations. Results: The best run, using in-context learning, achieved 0.58 document-level F1 score on publication abstracts and 0.75 document-level F1 score on clinical observations, as well as a mention-level F1 score of 0.7, which surpasses the current best in class tool. Without in-context learning, however, performance is significantly below the existing approaches. Conclusion: Our experiments show that gpt-4.0 surpasses the state of the art performance if the task is constrained to a subset of the target ontology where there is prior knowledge of the terms that are expected to be matched. While the results are promising, the non-deterministic nature of the outcomes, the high cost and the lack of concordance between different runs using the same prompt and input make the use of these LLMs challenging for this particular task. [ABSTRACT FROM AUTHOR]

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype–phenotype relations. [ABSTRACT FROM AUTHOR]

Background: Aboriginal and Torres Strait Islander people do not enjoy equal access to specialist health services that adequately meet their needs. Clinical genetics services are at the vanguard of realising the health benefits of genomic medicine. As the field continues to expand in clinical utility and implementation, it is critical that Aboriginal and Torres Strait Islander people are able to participate and benefit equally to avoid further widening of the existing health gap. This is the first study to explore barriers to accessing clinical genetics services among Aboriginal and Torres Strait Islander people, which has been acknowledged as a key strategic priority in Australian genomic health policy. Methods: A participatory design process engaged a majority-Aboriginal Project Reference Group and Aboriginal End-User Group. 63 semi-structured interviews were conducted with Aboriginal and/or Torres Strait Islander people who had accessed the government-funded clinical genetics service in Western Australia, Queensland or the Northern Territory between 2014 and 2018. The sample included patients, parents and carers. Participants were asked to recount their 'patient journey', from referral through to post-appointment and reflect on their perceptions of genetics and its implications for the health of themselves and their families. Analysis tracked chronological service engagement, followed by an inductive thematic approach. Results: Barriers to access and engagement were present at each stage of the patient journey. These included challenges in obtaining a referral, long waiting periods, limited genetic literacy, absence of Aboriginal support services, communication challenges and lack of adequate psychosocial support and follow-up after attendance. Participants' overall experiences of attending a genetic health service were varied, with positive perceptions tied closely to a diagnosis being achieved. The experience of (and expectation for) recognition of cultural identity and provision of culturally safe care was low among participants. Unaddressed concerns continued to cause significant distress in some people years after their appointment took place. Conclusions: There is significant scope for improving the care provided to Aboriginal and Torres Strait Islander people at clinical genetics services. Immediate attention to minimising logistical barriers, developing relationships with Aboriginal Community Controlled Health Services and providing practical and specific cultural safety training for practitioners is required at the service-level. Our findings strongly support the development of guidelines or policies recognising the collective cultural needs of Aboriginal and Torres Strait Islander people in relation to genomic health care. [ABSTRACT FROM AUTHOR]

Genomic testing for a genetic diagnosis is becoming standard of care for many children, especially those with a syndromal intellectual disability. While previously this type of specialised testing was performed mainly by clinical genetics teams, it is increasingly being 'mainstreamed' into standard paediatric care. With the introduction of a new Medicare rebate for genomic testing in May 2020, this type of testing is now available for paediatricians to order, in consultation with clinical genetics. Children must be aged less than 10 years with facial dysmorphism and multiple congenital abnormalities or have global developmental delay or moderate to severe intellectual disability. This rebate should increase the likelihood of a genetic diagnosis, with accompanying benefits for patient management, reproductive planning and diagnostic certainty. Similar to the introduction of chromosomal microarray into mainstream paediatrics, this genomic testing will increase the number of genetic diagnoses, however, will also yield more variants of uncertain significance, incidental findings, and negative results. This paper aims to guide paediatricians through the process of genomic testing, and represents the combined expertise of educators, clinical geneticists, paediatricians and genomic pathologists around Australia. Its purpose is to help paediatricians navigate choosing the right genomic test, consenting patients and understanding the possible outcomes of testing. [ABSTRACT FROM AUTHOR]

Background: Genomic sequencing in congenital heart disease (CHD) patients often discovers novel genetic variants, which are classified as variants of uncertain significance (VUS). Functional analysis of each VUS is required in specialised laboratories, to determine whether the VUS is disease causative or not, leading to lengthy diagnostic delays. We investigated stem cell cardiac disease modelling and transcriptomics for the purpose of genetic variant classification using a GATA4 (p.Arg283Cys) VUS in a patient with CHD. Methods: We performed high efficiency CRISPR gene editing with homology directed repair in induced pluripotent stem cells (iPSCs), followed by rapid clonal selection with amplicon sequencing. Genetic variant and healthy matched control cells were compared using cardiomyocyte disease modelling and transcriptomics. Results: Genetic variant and healthy cardiomyocytes similarly expressed Troponin T (cTNNT), and GATA4. Transcriptomics analysis of cardiomyocyte differentiation identified changes consistent with the patient's clinical human phenotype ontology terms. Further, transcriptomics revealed changes in calcium signalling, and cardiomyocyte adrenergic signalling in the variant cells. Functional testing demonstrated, altered action potentials in GATA4 genetic variant cardiomyocytes were consistent with patient cardiac abnormalities. Conclusions: This work provides in vivo functional studies supportive of a damaging effect on the gene or gene product. Furthermore, we demonstrate the utility of iPSCs, CRISPR gene editing and cardiac disease modelling for genetic variant interpretation. The method can readily be applied to other genetic variants in GATA4 or other genes in cardiac disease, providing a centralised assessment pathway for patient genetic variant interpretation. [ABSTRACT FROM AUTHOR]

Aim: To provide a birds-eye view of the trends of cerebral palsy (CP) for Australian Aboriginal and Torres Strait Islander children and young adults. Method: Data were obtained for this population-based observational study from the Australian Cerebral Palsy Register (ACPR), birth years 1995 to 2014. The Indigenous status of children was classified by maternal Aboriginal and Torres Strait Islander or non-Indigenous status. Descriptive statistics were calculated for socio-demographic and clinical characteristics. Prenatal/perinatal and post-neonatal birth prevalence was calculated per 1000 live births and per 10 000 live births respectively, and Poisson regression used to assess trends. Results: Data from the ACPR were available for 514 Aboriginal and Torres Strait Islander individuals with CP. Most children could walk independently (56%) and lived in urban or regional areas (72%). One in five children lived in socioeconomically disadvantaged remote/very remote areas. The birth prevalence of prenatal/perinatal CP declined after the mid-2000s from a high of 4.8 (95% confidence interval 3.2-7.0) to 1.9 per 1000 live births (95% confidence interval 1.1-3.2) (2013-2014), with marked declines observed for term births and teenage mothers. Interpretation: The birth prevalence of CP in Aboriginal and Torres Strait Islander children in Australia declined between the mid-2000s and 2013 to 2014. This birds-eye view provides key stakeholders with new knowledge to advocate for sustainable funding for accessible, culturally safe, antenatal and CP services. [ABSTRACT FROM AUTHOR]

Background: Childhood dementias are a group of rare and ultra-rare paediatric conditions clinically characterised by enduring global decline in central nervous system function, associated with a progressive loss of developmentally acquired skills, quality of life and shortened life expectancy. Traditional research, service development and advocacy efforts have been fragmented due to a focus on individual disorders, or groups classified by specific mechanisms or molecular pathogenesis. There are significant knowledge and clinician skill gaps regarding the shared psychosocial impacts of childhood dementia conditions. This systematic review integrates the existing international evidence of the collective psychosocial experiences of parents of children living with dementia. Methods: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched four databases to identify original, peer-reviewed research reporting on the psychosocial impacts of childhood dementia, from the parent perspective. We synthesised the data into three thematic categories: parents' healthcare experiences, psychosocial impacts, and information and support needs. Results: Nineteen articles met review criteria, representing 1856 parents. Parents highlighted extensive difficulties connecting with an engaged clinical team and navigating their child's rare, life-limiting, and progressive condition. Psychosocial challenges were manifold and encompassed physical, economic, social, emotional and psychological implications. Access to coordinated healthcare and community-based psychosocial supports was associated with improved parent coping, psychological resilience and reduced psychological isolation. Analysis identified a critical need to prioritize access to integrated family-centred psychosocial supports throughout distinct stages of their child's condition trajectory. Conclusion: This review will encourage and guide the development of evidence-based and integrated psychosocial resources to optimise quality of life outcomes for of children with dementia and their families. Key points: A synthesis of the shared psychosocial experiences and impacts of conditions causing childhood dementia is warranted. Parents share a tranche of overlapping challenges owing to limited access to psychosocial resources for their child's dementia condition. Severe neurocognitive decline is associated with higher parent psychological distress and isolation. Coordinated psychosocial interventions are required to improve outcomes for the family unit. Growing childhood dementia public awareness may activate earlier access to coordinated, sustainable and integrated supports. [ABSTRACT FROM AUTHOR]

Understanding hospital service use among children with a diagnosis of craniosynostosis (CS) is important to improve services and outcomes. This study aimed to describe population-level trends, patterns, and factors influencing hospitalizations for craniosynostosis in Western Australia. Data on live births (1990–2010; n = 554,624) including craniosynostosis, episodes of death, demographic, and perinatal factors were identified from the midwives, birth defects, hospitalizations, and death datasets. Information on craniosynostosis and non-craniosynostosis-related admissions, cumulative length of hospital stay (cLoS), intensive care unit, and emergency department–related admissions were extracted from the hospitalization dataset and linked to other data sources. These associations were examined using negative binomial regression presented as annual percent change and associations of hospitalizations by age groups, demographic, and perinatal factors were expressed as incidence rate ratio (IRR). We found an increasing trend in incident hospitalizations but a marginal decline in cLoS for craniosynostosis over the observed study period. Perinatal conditions, feeding difficulties, nervous system anomalies, respiratory, and other infections contributed to majority of infant non-CS-related admissions.Respiratory infections accounted for about twice the number of admissions for individuals with CS (IRRs 1.94–2.34) across all observed age groups. Higher incidence of non-CS hospitalizations was observed among females, with associated anomalies, to families with highest socioeconomic disadvantage and living in remote areas of the state. Conclusion: Marginal reduction in the cLoS for CS-related admissions observed over the 21-year period are potentially indicative of improved peri-operative care. However, higher incidence of respiratory infection-related admissions for syndromic synostosis is concerning and requires investigation. [ABSTRACT FROM AUTHOR]

Two million people in Australia live with a rare disease and face common challenges of diagnostic delay, lack of clinical knowledge and treatment and fragmented care, as well as significant psychosocial impacts. Caring for patients with rare diseases and their families requires innovative collaborative approaches across institutional, geographical and system boundaries. New resources and toolkits that prioritise improved diagnosis, care and support are available to help GPs provide excellence in rare disease care for patients and their families. [ABSTRACT FROM AUTHOR]

People living with rare diseases (PLWRD) still face huge unmet needs, in part due to the fact that care systems are not sufficiently aligned with their needs and healthcare workforce (HWF) along their care pathways lacks competencies to efficiently tackle rare disease-specific challenges. Level of rare disease knowledge and awareness among the current and future HWF is insufficient. In recent years, many educational resources on rare diseases have been developed, however, awareness of these resources is still limited and rare disease education is still not sufficiently taken into account by some crucial stakeholders as academia and professional organizations. Therefore, there is a need to fundamentally rethink rare disease education and HWF development across the whole spectrum from students to generalists, specialists and experts, to engage and empower PLWRD, their families and advocates, and to work towards a common coherent and complementary strategy on rare disease education and training in Europe and beyond. Special consideration should be also given to the role of nurse coordinators in care coordination, interprofessional training for integrated multidisciplinary care, patient and family-centered education, opportunities given by digital learning and fostering of social accountability to enforce the focus on socially-vulnerable groups such as PLWRD. The strategy has to be developed and implemented by multiple rare disease education and training providers: universities, medical and nursing schools and their associations, professional organizations, European Reference Networks, patient organizations, other organizations and institutions dedicated to rare diseases and rare cancers, authorities and policy bodies. [ABSTRACT FROM AUTHOR]

Abbreviations CDE Common data element; ICPGC International Cerebral Palsy Genomics Consortium; MDS Minimum data set; NINDS National Institute of Neurological Disorders and Stroke; PWG Phenotype Working Group Cerebral palsy (CP) is a clinically heterogeneous condition of movement, posture, and motor function attributed to a non-progressive and permanent disturbance to the fetal or infant brain.1 It is well recognized that the causal pathways to CP are complex and, in many cases, undefined. METHOD The development of the ICPGC CDEs for genomic studies of CP consisted of three phases: (1) a scoping review of the literature and development of the draft CDEs; (2) a modified, three-round Delphi process to achieve consensus on CDEs important for genomic studies of CP and to assign each data element to a hierarchal level based on their importance; and (3) development of the MDS (Figure S1). The data elements were scored against two criteria initially posited by the ICPGC-PWG as key requirements in the development of these CDEs: (1) is the data element important for genomic studies of CP; and (2) does the data element have an internationally standardized collection method, reporting variables or ontologies. [Extracted from the article]

Advances in genomic sequencing and genetic testing are increasingly transforming the diagnosis and treatment of diseases-specifically, rare diseases. However, the application and benefit of such technologies remain inequitable globally. There is a clear and urgent need to provide genomic sequencing to people across the global population, including people living in under-resourced areas and/or underrepresented populations. Financial considerations are the most obvious barriers to the adoption of genomic medicine, yet there are many other factors that are not so obvious, such as geography, language, communication, and culture. Herein, we use the lens of rare diseases and focus on firstly, selected socio-cultural factors, and in particular stigma; and secondly, empowering community factors such as education, advocacy and connectivity amongst people living with rare diseases globally. These are critical areas of need and opportunity if genomic medicine is to achieve equitable and global adoption in the patient best-interest across low- middle- and high-income country health systems. Furthermore, we touch on specific child health aspects and how they can point towards opportunities to build on specific infrastructures. [ABSTRACT FROM AUTHOR]

Silver-Russell syndrome (SRS) and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome are described in isolation. However, their co-occurrence has only been rarely reported. Here, we present a case report of an adolescent with SRS who was diagnosed with MRKH during the evaluation of primary amenorrhoea. Multiplex ligation-dependent probe amplification analysis showed a normal methylation pattern and normal dosage at 11p15.5. A PubMed search for all peer-reviewed publications (original articles and reviews) using the key words Silver-Russell syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, genetics, hypomethylation and reproductive anomalies identified three cases of SRS with MRKH, two of which were associated with significant hypomethylation of the H19 imprinting control region of the 11p15.5 locus. This report highlights the association between SRS and MRKH. The absence of hypomethylation and normal dosage at 11p15.5 suggests these two rare entities share alternative aetiopathogenic mechanisms. [ABSTRACT FROM AUTHOR]

Background: Over 400 million people worldwide are living with a rare disease. Next Generation Sequencing (NGS) identifies potential disease causative genetic variants. However, many are identified as variants of uncertain significance (VUS) and require functional laboratory validation to determine pathogenicity, and this creates major diagnostic delays. Methods: In this study we test a rapid genetic variant assessment pipeline using CRISPR homology directed repair to introduce single nucleotide variants into inducible pluripotent stem cells (iPSCs), followed by neuronal disease modelling, and functional genomics on amplicon and RNA sequencing, to determine cellular changes to support patient diagnosis and identify disease mechanism. Results: As proof-of-principle, we investigated an EHMT1 (Euchromatin histone methyltransferase 1; EHMT1 c.3430C > T; p.Gln1144*) genetic variant pathogenic for Kleefstra syndrome and determined changes in gene expression during neuronal progenitor cell differentiation. This pipeline rapidly identified Kleefstra syndrome in genetic variant cells compared to healthy cells, and revealed novel findings potentially implicating the key transcription factors REST and SP1 in disease pathogenesis. Conclusion: The study pipeline is a rapid, robust method for genetic variant assessment that will support rare diseases patient diagnosis. The results also provide valuable information on genome wide perturbations key to disease mechanism that can be targeted for drug treatments. [ABSTRACT FROM AUTHOR]

Introduction: The goal of this study was to understand individuals with cerebral palsy (CP) and their family's attitudes and preferences to genomic research, including international data sharing and biobanking. Methods: Individuals with CP and their family members were invited to participate in the web-based survey via email (NSW/ACT CP Register) or via posts on social media by Cerebral Palsy Alliance, CP Research Network, and CP Now. Survey responses included yes/no/unsure, multiple choices, and Likert scales. Fisher's exact and χ2 tests were used to assess if there were significant differences between subgroups. Results: Individuals with CP and their families (n = 145) were willing to participate in genomics research (68%), data sharing (82%), and biobanking efforts (75%). This willingness to participate was associated with completion of tertiary education, previous genetic testing experience, overall higher genomic awareness, and trust in international researchers. The survey respondents also expressed ongoing communication and diverse information needs regarding the use of their samples and data. Major concerns were associated with privacy and data security. Discussion: The success of genomic research and international data sharing efforts in CP are contingent upon broad support and recruitment. Ongoing consultation and engagement of individuals with CP and their families will facilitate trust and promote increased awareness of genomics in CP that may in turn maximize participant uptake and recruitment. [ABSTRACT FROM AUTHOR]

This letter discusses an initiative that considered the rights of a child living with a rare disease in the context of the United Nations Convention on the Rights of the Child (UNCRC). The aim was to inform laypeople on the intersection between the UNCRC and rare and undiagnosed diseases. The Project was initiated in Western Australia for a national audience, with a view that it might also provide a framework that is translatable to other jurisdictions internationally. This letter discusses some of the key themes raised by the Project and the potential for further work. [ABSTRACT FROM AUTHOR]

Aim: To describe the birth prevalence and characteristics of congenital heart defects in a geographically defined Australian population. Methods: This descriptive, population‐based study examined congenital heart defects in live births, stillbirths and pregnancy terminations ascertained by the Western Australian Register of Developmental Anomalies, 1990–2016. Birth prevalence (per 1000 births) was stratified by severity, known cause, maternal and birth characteristics, and primary diagnosis; and prevalence ratios were calculated for Aboriginal versus non‐Aboriginal births. Temporal trends in prevalence, diagnosis age and infant mortality were examined. Results: For births 1990–2010 (allowing 6 years for complete case ascertainment by 2016), 6419 cases were identified; prevalence was 11.5 per 1000 births (95% confidence interval (CI), 11.2–11.8). Severe defects were ascertained in 2.5 per 1000 births (95% CI 2.4–2.7). Most cases were liveborn (5842, 91.0%), and 28.9% had other birth defects. Prevalence was slightly higher in Aboriginal births (prevalence ratio 1.1; 95% CI 1.0–1.2); and the infant mortality rate more than doubled (13.4% vs. 5.8%, P < 0.001). Prenatal diagnosis increased over time but, in remote areas, was significantly lower for Aboriginal versus non‐Aboriginal cases (3.1% vs. 9.3%; P = 0.008). A cause was identified in 920 cases (14.3%), more often for severe defects (347, 24.4%); 63% of known causes were rare diseases. Congenital heart defects associated with fetal alcohol spectrum disorder were much more common in Aboriginal births (prevalence ratio 82; 95% CI 28–239). Conclusions: Earlier detection of congenital heart defects and improved survival has occurred over time, although discrepancies between ethnic groups and regions warrant further investigation and strategic action. [ABSTRACT FROM AUTHOR]

We report three babies from two families with a severe lethal form of congenital cutis laxa. All three had redundant and doughy‐textured skin and two siblings from one family had facial dysmorphism. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity. Post‐mortem examination in two of the babies further revealed widespread ectasia and tortuosity of medium and large sized arteries, myocardial hypertrophy, rib and skull fractures. The presence of fractures initially suggested a diagnosis of osteogenesis imperfecta. Under light microscopy bony matrices were abnormal and arterial wall architecture was grossly abnormal showing fragmented elastic fibres. Molecular analysis of known cutis laxa genes did not yield any pathogenic defects. Whole exome sequencing of DNA following informed consent identified two separate homozygous variants in the LOX (Lysyl Oxidase) gene. LOX belongs to the 5‐lysyl oxidase gene family involved in initiation of cross‐linking of elastin and collagen. A mouse model of a different variant in this gene recapitulates the phenotype seen in the three babies. Our findings suggest that the LOX gene is a novel cause of severe congenital cutis laxa with arterial tortuosity, bone fragility and respiratory failure. [ABSTRACT FROM AUTHOR]

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories. [ABSTRACT FROM AUTHOR]

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories. [ABSTRACT FROM AUTHOR]

Background: Indigenous people tend to exhibit a higher burden of disability than their non-Indigenous counterparts, and are often underserved by disability services. Engaging appropriately with Indigenous communities, families and individuals in the initial stages of disability assessment and planning is crucial in order to build trust and understanding of disability service models and ensure that Indigenous people receive support that is tailored to their needs and cultural realities. This article aims to identify key elements of culturally competent communication in Indigenous disability assessment and planning, and provide recommendations for strengthening capacity in this area. Methods: This qualitative research was designed to involve Aboriginal and Torres Strait Islander people at all stages and to reflect the views of Aboriginal and Torres Strait Islander researchers, people and families affected by disability and the community-controlled health sector. Semi-structured individual interviews were undertaken with staff implementing the National Disability Insurance Scheme (NDIS) (n = 4), NDIS participants (n = 24), disability support providers and organisational partners (n = 19) and Community Connectors (n = 8) in Queensland and the Northern Territory of Australia. Key themes derived from thematic analysis included appropriate and adequate engagement of individuals with disability and their families, the role of trusted relationships, and culturally safe and appropriate communication during planning meetings. Results: Overall, the research findings highlight that a low level of cultural competence in the initial stages of the disability assessment and planning process exacerbated participant confusion and distrust towards assessment staff and the NDIS. Given difficulties in communication, participant understanding of the NDIS was generally limited. The necessity of culturally safe and appropriate use of interpreters was stressed, as was the role of trusted individuals, including existing service providers, Community Connectors and family members in providing a solid base for participant understanding of the NDIS. Conclusions: Cultural competence in disability assessment and planning can be strengthened through multi-level engagement with the Aboriginal community-controlled sector and community leaders. Implementing mechanisms to enable the involvement of families, trusted service providers and Community Connectors can support a more meaningful understanding of individuals' needs within their cultural context and in relation to their cultural roles. [ABSTRACT FROM AUTHOR]

Background: Aboriginal and Torres Strait Islander people experience a greater burden of disease and die younger than non-Indigenous Australians, with Aboriginal people living in remote areas of the Northern Territory of Australia having the lowest life expectancy estimates. Despite a high burden of chronic disease among Aboriginal and Torres Strait Islander people, access to specialist health services remains low and models of care that increase engagement, may improve health outcomes. Methods: We describe client and staff perspectives of a model of clinical genetics services provided by the MJD Foundation (MJDF) in geographically and culturally complex contexts within the Northern Territory of Australia. We seek to understand the MJDF model's success in supporting Aboriginal families with the familial, neurodegenerative condition Machado-Joseph disease and how it could be applied in the provision of other specialist services. Thematic analysis was undertaken on semi-structured interviews with primary health care staff (n = 2), Non-Aboriginal MJDF Staff (n = 7) and Aboriginal MJDF Clients / Community workers (n = 13). Results: Four key themes regarding the MJDF model of service delivery were identified with the service being; 1) client led 2) accepting of various understandings of genetic disease causation 3) focused on relationships, continuity and trust between the service provider and the clients, and 4) committed to incorporating an inclusive whole-of-family practice. The MJDF model takes a community-based, person-and family-centred approach to successfully deliver effective specialist genetic health services in remote community settings. We propose that these approaches have broad application in the future design and delivery of specialist health services particularly in culturally complex settings. [ABSTRACT FROM AUTHOR]

High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as "cerebral palsy." This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology. [ABSTRACT FROM AUTHOR]

The article discusses the causes of cerebral palsy (CP). Topics discussed include intrapartum complications as the primary cause of CP; clinical risk factors like preterm birth, presence of congenital anomalies, and fetal growth restriction; and genomics embraced by medical practice. Also being discussed is the platform provided by international consortium for genomic research.

The introduction of exome sequencing in the clinic has sparked tremendous optimism for the future of rare disease diagnosis, and there is exciting opportunity to further leverage these advances. To provide diagnostic clarity to all of these patients, however, there is a critical need for the field to develop and implement strategies to understand the mechanisms underlying all rare diseases and translate these to clinical care. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To examine whether children conceived using assisted reproductive technology (ART) have a higher risk of intellectual disability (ID) compared with non-ART-conceived children and describe known causes of ID in these groups. METHODS: We linked ID and ART data from population-based registers in Western Australia. Our cohort included live births from 1994 to 2002 (n = 210 627) with at least 8 years of follow-up. The prevalence of ID was compared between ART- and non-ART-conceived children, and risk of ID was estimated using Poisson regression with robust SEs. We also stratified by plurality and gestation at delivery. RESULTS: Children conceived using ART had a small increased risk of ID (risk ratio 1.58; 95% confidence interval 1.19-2.11) even when analyses were restricted to singleton births (risk ratio 1.56; 95% confidence interval 1.10-2.21). The risk of ID was more than doubled for those born very preterm, for severe ID, and after intracytoplasmic sperm injection (ICSI) treatments. Children conceived using ICSI had a greater risk of ID than those conceived using in vitro fertilization and were more likely to have a known genetic cause for ID (27.6% vs 12.9% in vitro fertilization and 11.9% non-ART). CONCLUSIONS: The risk of ID was increased in children born after ART in Western Australia from 1994 to 2002. More recent cohorts should be examined to assess the impact of important changes in ART clinical practice. Our results are particularly pertinent because multiple embryo transfers are routinely performed in many countries, increasing the risk of preterm birth, and ICSI use rates are high. [ABSTRACT FROM AUTHOR]

The article discusses the progress in rare diseases research from 2010 to 2016 according to the International Rare Diseases Research Consortium (IRDiRC). Topics discussed include the definition of rare diseases, the success of the introduction of regulatory and economic incentives in successfully attracting the biopharmaceutical industry, and history and governance of the IRDiRC.

The article discusses the future of rare diseases research according to the International Rare Diseases Research Consortium (IRDiRC). Topics include factors that led to the realization regarding the need for global cooperation and collaboration in rare diseases research, the role of the IRDiRC in raising public awareness about rare diseases, and goals of the IRDiRC for rare diseases research from 2017 to 2027.

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population. [ABSTRACT FROM AUTHOR]

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD. [ABSTRACT FROM AUTHOR]

The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. [ABSTRACT FROM AUTHOR]

• CRISPR gene editing for gene haploinsufficiency. • High throughput clone selection of CRISPR edited cells. • Rare disease genetic variant assessment in HEK293 cells. • Identified changes in molecular pathways relevant to disease phenotype. There are an estimated > 400 million people living with a rare disease globally, with genetic variants the cause of approximately 80% of cases. Next Generation Sequencing (NGS) rapidly identifies genetic variants however they are often of unknown significance. Low throughput functional validation in specialist laboratories is the current ad hoc approach for functional validation of genetic variants, which creating major bottlenecks in patient diagnosis. This study investigates the application of CRISPR gene editing followed by genome wide transcriptomic profiling to facilitate patient diagnosis. As proof-of-concept, we introduced a variant in the Euchromatin histone methyl transferase (EHMT1) gene into HEK293T cells. We identified changes in the regulation of the cell cycle, neural gene expression and suppression of gene expression changes on chromosome 19 and chromosome X, that are in keeping with Kleefstra syndrome clinical phenotype and/or provide insight into disease mechanism. This study demonstrates the utility of genome editing followed by functional readouts to rapidly and systematically validating the function of variants of unknown significance in patients suffering from rare diseases. [ABSTRACT FROM AUTHOR]

Concept recognition tools rely on the availability of textual corpora to assess their performance and enable the identification of areas for improvement. Typically, corpora are developed for specific purposes, such as gene name recognition. Gene and protein name identification are longstanding goals of biomedical text mining, and therefore a number of different corpora exist. However, phenotypes only recently became an entity of interest for specialized concept recognition systems, and hardly any annotated text is available for performance testing and training. Here, we present a unique corpus, capturing text spans from 228 abstracts manually annotated with Human Phenotype Ontology (HPO) concepts and harmonized by three curators, which can be used as a reference standard for free text annotation of human phenotypes. Furthermore, we developed a test suite for standardized concept recognition error analysis, incorporating 32 different types of test cases corresponding to 2164 HPO concepts. Finally, three established phenotype concept recognizers (NCBO Annotator, OBO Annotator and Bio-LarK CR) were comprehensively evaluated, and results are reported against both the text corpus and the test suites. The gold standard and test suites corpora are available from http://bio-lark.org/hpo_res.html. [ABSTRACT FROM AUTHOR]

Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers. [ABSTRACT FROM AUTHOR]