ABSTRACT
The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23-Glu-Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).
ABSTRACT
Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.
Subject(s)
DNA Methylation , Intellectual Disability , Humans , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Male , Female , Haploinsufficiency/genetics , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/diagnosis , ChildABSTRACT
BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Subject(s)
Aniridia , Carbonic Anhydrases , Cerebellar Ataxia , Intellectual Disability , Movement Disorders , Spinocerebellar Degenerations , Humans , Cerebellar Ataxia/genetics , Mutation, Missense/genetics , Movement Disorders/complications , Atrophy , Inositol 1,4,5-Trisphosphate Receptors/chemistry , Inositol 1,4,5-Trisphosphate Receptors/genetics , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Carbonic Anhydrases/genetics , Carbonic Anhydrases/metabolism , Intracellular Signaling Peptides and Proteins/geneticsABSTRACT
Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.
Subject(s)
Hypogonadism , Intellectual Disability , Mental Retardation, X-Linked , Male , Humans , Female , Intellectual Disability/genetics , Mental Retardation, X-Linked/genetics , Hypogonadism/genetics , Hypogonadism/complications , Hypogonadism/diagnosis , Obesity/geneticsABSTRACT
BACKGROUND: Pfeiffer syndrome is characterized by craniosynostosis, mid-face hypoplasia, broad thumbs, and often multilevel airway obstruction. Airway management is often required, including the use of positive airway ventilation, nasopharyngeal airway (NPA), or tracheostomy. OBJECTIVE: The objective of this study was to assess the impact an airway adjunct can have on feeding difficulties in children with Pfeiffer syndrome. METHODS: Retrospective review of patients diagnosed with Pfeiffer syndrome from January 1998 to January 2020 at one of England's 4 supraregional Craniofacial Units, Alder Hey Children's Hospital. Speech & Language Therapy case notes and medical notes were used to gather data, as well as the Oral Feeding Score component of the UK Craniofacial Outcome Score. RESULTS: Eleven patients were included. Six patients had no airway adjunct (55%): 3 had tracheostomy (27%) and 2 patients had NPA (18%). All patients with airway adjuncts were percutaneous endoscopic gastrostomy/percutaneous endoscopic jejunostomy fed. Those who did not require an airway adjunct had an Oral Feeding Score of 4.60 (SD: 0.49). The children who went on to have an airway adjunct had a mean preintervention Oral Feeding Score of 2.4 (SD: 0.8). The mean feeding score (postairway adjunct) in the NPA group was 2.0, compared with the tracheostomy group scoring 3.0. CONCLUSIONS: Children with Pfeiffer syndrome who require airway intervention have more significant feeding problems requiring feeding intervention. Although there were small numbers included in this study, there is a suggestion that airway adjuncts can contribute to feeding difficulties, particularly NPAs.
Subject(s)
Acrocephalosyndactylia , Airway Obstruction , Humans , Child , Infant , Acrocephalosyndactylia/surgery , Airway Management , Airway Obstruction/surgery , Nasopharynx , Tracheostomy , Retrospective StudiesABSTRACT
Inherited kidney disease accounts for a significant proportion of chronic kidney disease and end-stage renal failure. There is increasing evidence that genetic testing for inherited kidney disease should be integrated into clinical care pathways at the earliest opportunity so that patients and their families can maximally benefit from carefully tailored care. Despite increased availability of genetic testing, the proportion of patients with renal disease undergoing genetic investigations remains low. This article introduces key concepts of genetic and genomic testing to the renal physician and addresses some common barriers to the wider integration of genetic testing in routine clinical practice to fully capitalise on recent advances in genomic medicine and improve patient outcomes.
Subject(s)
Kidney Failure, Chronic , Renal Insufficiency, Chronic , Humans , Kidney , Genetic Testing , Kidney Failure, Chronic/genetics , GenomicsABSTRACT
The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.
Subject(s)
Epilepsy , Vacuolar Proton-Translocating ATPases , Humans , Vacuolar Proton-Translocating ATPases/genetics , Vacuolar Proton-Translocating ATPases/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Epilepsy/genetics , Adenosine TriphosphateABSTRACT
INTRODUCTION: Apert syndrome is a multisystem genetic disorder typically characterized by craniosynostosis and syndactyly. Studies also report an increased incidence of hearing loss in children with Apert syndrome in comparison to the general population. The aim of this study was to gain an understanding of the inner ear radiological anatomical variations seen in children with Apert syndrome and correlate these with audiological outcomes. MATERIALS AND METHODS: This was a retrospective review of computed tomography imaging of patients with Apert syndrome. Radiological images were examined for anatomical variations in inner ear structures. These were correlated with audiological testing. RESULTS: Nineteen patients were included in the study. The most commonly observed anomaly was an absent bony window of the lateral semi-circular canal (SCC) in 11 patients (58%), followed by an enlarged lateral SCC in 12 patients (63%). This combination of anomalies was seen collectively in 42% of patients and together these give the appearance of a 'rectangular vestibular cavity'. Audiological results were available in 11 patients and 9 of these patients had a conductive hearing loss. CONCLUSION: To the authors' knowledge, this is the first study that reports radiological findings alongside audiological testing in Apert syndrome and describes the appearance of a 'rectangular vestibular cavity'.
Subject(s)
Acrocephalosyndactylia , Craniosynostoses , Ear, Inner , Hearing Loss, Sensorineural , Hearing Loss , Acrocephalosyndactylia/complications , Acrocephalosyndactylia/diagnostic imaging , Child , Craniosynostoses/complications , Ear, Inner/abnormalities , Ear, Inner/diagnostic imaging , Hearing Loss/complications , Hearing Loss, Conductive/etiology , Hearing Loss, Sensorineural/etiology , Humans , Retrospective StudiesABSTRACT
BACKGROUND: It is critical that mental health systems place a focus on prevention and early intervention focused on young people while integrating youth voice to guide priority directions. OBJECTIVE: This study was designed to better understand how youth advisories can be utilized to influence strategic directions within integrated knowledge mobilization networks operating within the youth mental health system. DESIGN: To support this objective, we reviewed the detailed stages of development in establishing a youth advisory within a national network designed to support the integration of youth services. We also engaged the advisory in a participatory evaluation process that examined the extent to which the network had created processes to include youth voice in decision-making. RESULTS: Results from the surveys identified moderate to high levels of individual engagement as well as strong development of processes and procedures that support the inclusion of youth voice across the network. DISCUSSION: Major successes and challenges are presented and discussed with respect to the development of the advisory. The findings are useful for youth advocates and adult allies working to support youth engagement (YE) in knowledge mobilization to enhance the mental health services system. This study also contributes to research and evaluation efforts examining YE and represents an exemplar methodology for evaluating YE efforts at the system level. PATIENT OR PUBLIC CONTRIBUTION: Young people as mental health service users and youth mental health advocates were involved in the design, data collection, analysis and interpretation of the data as well as the preparation of this manuscript.
Subject(s)
Mental Health Services , Adolescent , Adult , Humans , Mental Health , Social Networking , Surveys and QuestionnairesABSTRACT
Youth accessing mental health care often experience a disruption in care as they attempt to transition between child and adolescent mental health services (CAMHS) and adult mental health services (AMHS). Few studies have evaluated interventions seeking to improve the experience and outcomes of CAMHS-AMHS transitions, in part due to lack of consensus on what constitutes best practices in intervention success. As such, the aim of this study was to engage patients, caregivers, and clinicians to prioritize core components of successful CAMHS-AMHS transitions which can be used in the design or evaluation of transition interventions. As such, a Delphi study was conducted to determine core components of successful CAMHS-AMHS transitions. Guided by the principles of patient-oriented research, three balanced expert panels consisting of youth, caregivers, and clinicians ranked and provided feedback on the importance and feasibility of core components of CAMHS-AMHS transitions. Components endorsed as feasible or important with ≥ 70% agreement from any panel moved to the next round. As a result, a list of 26 core components of CAMHS-AMHS transitions has been refined which can be used in the design, implementation, or evaluation of interventions intended to improve transition experiences and outcomes for youth in mental health care. Youth and families were engaged in an expert advisory role throughout the research process, contributing their important perspectives to the design and implementation of this study, as well as interpretation of the findings.
Subject(s)
Adolescent Health Services , Mental Disorders , Transition to Adult Care , Adult , Child , Humans , Adolescent , Mental Disorders/therapy , Mental Disorders/psychology , Caregivers , Mental HealthABSTRACT
PURPOSE: Genome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease. METHODS: GS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP. RESULTS: Sixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%), and copy-number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%). CONCLUSION: GS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximize the potential of clinical GS.
Subject(s)
Craniosynostoses , Genetic Testing , Base Sequence , Chromosome Mapping , Craniosynostoses/diagnosis , Craniosynostoses/genetics , Humans , Rare Diseases/geneticsABSTRACT
INTRODUCTION: Transition from child and adolescent mental health services (CAMHS) to community or adult mental health services (AMHS) is a highly problematic health systems hurdle, especially for transition-aged youth. A planned and purposeful transition process is often non-existent or experienced negatively by youth and their caregivers. Stakeholders, including youth and their caregivers, have demanded interventions to support more effective transitions, such a transition navigator. The transition navigator model uses a navigator to facilitate complex transitions from acute care CAMHS to community or AMHS. However, despite the widespread implementation of this model, there has been no evaluation of the programme, hindering its scalability. This paper describes the study protocol of the Navigator Evaluation Advancing Transitions study that aims to collaborate with patients, caregivers and clinicians in the evaluation of the navigator model. METHODS AND ANALYSIS: A pre and post mixed-method study will be conducted, using the Triple Aim Framework, to evaluate the navigator model. We will recruit participants from one large tertiary and two community hospitals in Toronto, Canada. For the quantitative portion of the study, we will recruit a sample of 45 youth (15 at each site), aged 16-18, and their caregivers at baseline (referral to navigator) (T1) and 6 months (T2). Youth and caregiver participants will complete a set of standardised measures to assess mental health, service utilisation, and satisfaction outcomes. For the qualitative portion of the study, semistructured interviews will be conducted at 6 months (T2) with youth, their caregivers and clinicians to better understand their experience and satisfaction with the model. ETHICS AND DISSEMINATION: Research Ethics Board (REB) approval has been obtained from the lead research sites, the University of Toronto and the Hospital for Sick Children. The results of the study will be reported in peer-reviewed publications, webinars and conferences and to all relevant stakeholders.
Subject(s)
Adolescent Health Services , Mental Health Services , Transition to Adult Care , Adolescent , Adult , Canada , Child , Health Transition , HumansABSTRACT
Radiotherapy is a regimen that uses ionising radiation (IR) to treat cancer. Despite the availability of several therapeutic options, cancer remains difficult to treat and only a minor percentage of patients receiving radiotherapy show a complete response to the treatment due to development of resistance to IR (radioresistance). Therefore, radioresistance is a major clinical problem and is defined as an adaptive response of the tumour to radiation-induced damage by altering several cellular processes which sustain tumour growth including DNA damage repair, cell cycle arrest, alterations of oncogenes and tumour suppressor genes, autophagy, tumour metabolism and altered reactive oxygen species. Cellular organelles, in particular mitochondria, are key players in mediating the radiation response in tumour, as they regulate many of the cellular processes involved in radioresistance. In this article has been reviewed the recent findings describing the cellular and molecular mechanism by which cancer rewires the function of the mitochondria and cellular metabolism to enhance radioresistance, and the role that drugs targeting cellular bioenergetics have in enhancing radiation response in cancer patients.
ABSTRACT
The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.
Subject(s)
ATPases Associated with Diverse Cellular Activities/genetics , Endosomal Sorting Complexes Required for Transport/genetics , Mutation, Missense , Neurodevelopmental Disorders/genetics , Vacuolar Proton-Translocating ATPases/genetics , Alleles , Animals , Brain/abnormalities , Cell Cycle , Centrosome/metabolism , Endosomes/metabolism , Fibroblasts/metabolism , Genomics , HEK293 Cells , HeLa Cells , Humans , Mice , Neurons/metabolism , Protein Domains , Protein Transport , Spindle Apparatus/metabolismABSTRACT
Pathogenic variants in the nonimprinted in Prader-Willi/Angelman syndrome (NIPA1) gene typically present with pure hereditary spastic paraplegia (HSP) but complex cases are described. We present a patient with childhood idiopathic generalised epilepsy (IGE) who later developed HSP. She rapidly deteriorated 27 years later with clinically definite amyotrophic lateral sclerosis (ALS). Her family history included HSP, IGE and motor neurone disease. Genetic testing identified a pathogenic variant in the NIPA1 gene associated with spastic paraplegia 6 (SPG6). This case provides the first description of NIPA1 in a family with epilepsy, ALS and thus complex HSP.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Epilepsy/genetics , Membrane Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Amyotrophic Lateral Sclerosis/complications , Epilepsy/complications , Fatal Outcome , Female , Genetic Testing , Genetic Variation , Heterozygote , Humans , Middle Aged , Pedigree , Phenotype , Spastic Paraplegia, Hereditary/complicationsABSTRACT
BACKGROUND: Mental health issues presenting in childhood often persist into adulthood, usually requiring youth to transition from child and adolescent mental health services to adult mental health services at 18 years. Discontinuity of care during this transition period is well-documented and can leave youth vulnerable to adverse mental health outcomes. There is growing recognition of the need to improve transition-related care for youth leaving the child and adolescent mental health system. However, the perspectives and experiences of youth have not always been forefront in these discussions, and in particular, the perspectives of youth in the pre-transition period. This study qualitatively explores transition-related knowledge and experiences of youth both prior-to and after transition. METHODS: A purposive sample of youth aged 16-19 years was recruited from two child and adolescent mental health programs. Youth were enrolled as part of a longitudinal follow-up study and had the opportunity to opt into this study. Interviews were transcribed and coded using NVivo11 software. Main themes were distilled through descriptive analysis following the principles of directed content analysis. The study followed the principles of participatory action research, engaging youth with lived experience navigating transitions in each stage of the study. RESULTS: In-depth, semi-structured interviews were conducted with 14 pre-transition and 8 post-transition youth. All youth reported having either a mood and/or anxiety disorder for which the majority were receiving treatment at the time of the interview. The participants' experiences were distilled into six major themes. Youth advocated for being considered partners in transition planning and to have increased control over transition-related decisions. Youth also made specific recommendations on how to improve continuity of care during the transition process. CONCLUSIONS: Transition planning should be individualized for each youth based on their developmental needs, transition readiness and ongoing mental health needs. Transition pathways, co-designed with youth and caregivers, should be developed to guide providers in transition best practices. Obtaining both the pre- and post-transition experiences of youth is crucial for developing a more complete of understanding of youth perspectives and implementing guidelines that improve transition quality and experiences.
Subject(s)
Adolescent Health Services/statistics & numerical data , Mental Disorders/psychology , Mental Health Services/statistics & numerical data , Transition to Adult Care/statistics & numerical data , Adolescent , Adult , Anxiety Disorders/psychology , Anxiety Disorders/therapy , Child , Female , Follow-Up Studies , Humans , Interviews as Topic , Male , Mental Disorders/therapy , Physician-Patient Relations , Qualitative Research , Young AdultABSTRACT
Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
Subject(s)
Phenotype , Sotos Syndrome/physiopathology , Adult , Child , Facies , Female , Humans , Intellectual Disability/genetics , Male , Sotos Syndrome/genetics , Sotos Syndrome/psychologyABSTRACT
Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.
Subject(s)
Developmental Disabilities/genetics , Mutation , RNA Splice Sites , Exome , Humans , Exome SequencingABSTRACT
CONTEXT: Engaging youth as partners in academic research projects offers many benefits for the youth and the research team. However, it is not always clear to researchers how to engage youth effectively to optimize the experience and maximize the impact. OBJECTIVE: This article provides practical recommendations to help researchers engage youth in meaningful ways in academic research, from initial planning to project completion. These general recommendations can be applied to all types of research methodologies, from community action-based research to highly technical designs. RESULTS: Youth can and do provide valuable input into academic research projects when their contributions are authentically valued, their roles are clearly defined, communication is clear, and their needs are taken into account. Researchers should be aware of the risk of tokenizing the youth they engage and work proactively to take their feedback into account in a genuine way. Some adaptations to regular research procedures are recommended to improve the success of the youth engagement initiative. CONCLUSIONS: By following these guidelines, academic researchers can make youth engagement a key tenet of their youth-oriented research initiatives, increasing the feasibility, youth-friendliness and ecological validity of their work and ultimately improve the value and impact of the results their research produces.