Commentary: Taking stock and moving forward - the need to consider the influence of loss to follow-up in autism screening research.

This commentary highlights the limitations of many existing population-based studies examining the utility of the Modified Checklist for Autism in Toddlers, Revised/Follow-Up (M-CHAT-R/F) in screening for autism. We expound on three major factors: (a) the limited number of screen-negative children who undergo diagnostic evaluations, (b) the substantial number of children who screen positive and were subsequently lost to follow-up (i.e. without further diagnostic evaluations), and (c) the sizeable number of children who did not complete the full two-stage screening process as intended. Each of these factors can lead to erroneous estimates of the psychometric properties, specifically, the sensitivity, specificity, and negative predictive value. Hence, we emphasize the need for future studies to increase the number of children who screen negative and receive a diagnostic evaluation and ensure that these children are selected at random without a higher likelihood for the presence of autism. It is also imperative that concrete steps are taken to minimize the number of screen-positive children who are lost to follow-up both within and after the screening process. Both of these will play a major role in ensuring more robust results from empirical research that can guide the clinical implementation of the M-CHAT-R/F.

Qualitative study on barriers and coping strategies for dental care in autistic children: Parents' perspective.

BACKGROUND: Children with autism spectrum disorders (ASD) face challenges in home oral care, accessing a dentist and accepting dental treatment. AIM: To determine the barriers to dental care for autistic children in Singapore through the experiences and opinions of their parents. DESIGN: A qualitative exploratory approach comprising semistructured interviews and a focus group discussion was used. Audio recordings were transcribed and coded into themes using NVivo 12 software. RESULTS: Participants were 23 parents of autistic children aged 3-12 years. The following barriers were identified: (1) Sensory, physical and parental knowledge issues are related to toothbrushing difficulties and use of nonoptimally fluoridated toothpaste in autistic children. (2) Accessing dental services was hindered by a lack of parental knowledge on the importance of an early dental home, parental apprehension about the child's acceptance of dental care, lack of information on specialised dentists and perceived high cost of dental visits. Parental suggestions for improvements included understanding the child's sensory profile, more information on finding a suitable dentist and subsidisation of costs for multiple acclimatisation visits. CONCLUSION: Caregivers' education, information about specialised dentists and the availability of specific dental care resources for autistic children in Singapore are needed for optimising their dental care.

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990-2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

Occupational and speech therapists' perceptions of their role in dental care for children with autism spectrum disorder: A qualitative exploration.

BACKGROUND: Children with autism spectrum disorder (ASD) have challenges in home oral care, accessing a dentist and accepting dental treatment. Occupational therapists (OTs) and speech therapists (STs) are likely to be involved earlier in managing communication, behavioural and sensory processing issues. AIM: To determine perceived issues, barriers and potential solutions to dental care for children with ASD in Singapore from the perspective of OTs and STs. DESIGN: Semi-structured interviews and a focus group discussion involving OTs and STs who treat children with ASD were conducted. Audio recordings were transcribed and coded into themes using the NVivo 12 software. RESULTS: Emergent themes indicated that: (i) OTs and STs have important roles in recognition of issues with toothbrushing, oral pathology and harmful oral habits; (ii) OTs and STs were able to identify reasons for difficulties in oral home care for children with ASD and offer helpful strategies; and (iii) OTs and STs can play a role in pre-dental visit preparations but lack a clear dental referral pathway. CONCLUSIONS: OTs and STs exclusively assist in the early identification and referrals of children with ASD to the dentist. Interprofessional collaboration with dentists should be further explored to aid in the provision of preventive dental advice.

Families With Children With Neurodevelopmental Disorders During COVID-19: A Scoping Review.

OBJECTIVE: Prolonged home isolation may lead to long-term negative consequences for both children and caregivers' psychological wellbeing, especially in families with children with neurodevelopmental disorders. Therefore, a scoping review was conducted to identify challenges faced by caregivers of children with neurodevelopmental disorders during the coronavirus disease 2019 (COVID-19) pandemic and to consolidate parenting interventions and guidelines. METHODS: A systematic search was conducted on Embase, PsycInfo, PubMed, Scopus, and LitCovid. All article types published between December 2019 and November 2020 which reported on intervention guidelines and experiences of families with children with neurodevelopmental disorders during the COVID-19 pandemic were included. Qualitative themes, quantitative data, and article summaries were charted, and a thematic analysis was conducted. RESULTS: Twenty-nine articles were included in the review. Three themes were generated: (a) behavioral issues and health concerns, (b) disruptions of lifelines and daily routines, and (c) existing programs, models, and guidelines to support families. Additionally, a list of caregiver strategies such as scheduling regular online consultations, maintaining online therapy, educating a child on COVID-19, and preventive behaviors, creating a structured daily schedule and reinforcement system, and selecting child-appropriate activities was consolidated. CONCLUSION: This review revealed a lack of evidence-based studies and articles on children with other neurodevelopmental disorders apart from autism and attention-deficit hyperactivity disorder. It also places emphasis on the importance of telehealth services as major lifelines to parents during this pandemic and urges healthcare organizations to provide funding to increase telehealth services to afflicted families.

Juggling Multiple Roles amidst Uncertainty: The Asian Father's Perspective of an Infant in Neonatal Intensive Care Unit.

OBJECTIVE: Parents of preterm, very low birthweight (VLBW) infants in neonatal intensive care units (NICU) undergo emotional turmoil. Studies on parent's experiences typically focus on the maternal perspective. The purpose of the study is to explore the emotional needs and experiences of fathers of VLBW neonates in the NICU and to identify ways to improve their experiences. STUDY DESIGN: This was a qualitative descriptive design study undertaken at the NICU of a tertiary university hospital. Convenience sampling with predefined inclusion and exclusion criteria was used to identify prospective participants. Semi-structured interviews were conducted with 15 fathers of infants until data saturation was reached. The COREQ (Consolidated Criteria for Reporting Qualitative Studies) checklist was used. RESULTS: Father's experiences were classified into the topics of concerns, roles, and perspectives. Uncertainty was a predominant theme in each of these. Fathers assume multiple roles toward the child, wife, self, and family. Their concerns were multifaceted involving the child, family, work, and finances; they experienced a myriad of emotions, but these evolved into resilience eventually. CONCLUSION: Fathers have unique concerns pertinent to having an infant in the NICU. They juggle multiple roles and transition to emotions of resilience. It is imperative to acknowledge the uncertainty and diverse roles of fathers, provide them with customized information, and develop more balanced parent-support groups. KEY POINTS: · Fathers juggle multiple roles with a child in NICU.. · Uncertainty is a key part of their experience.. · Acknowledging their role and emotions is important..

A qualitative study exploring experiences and support needs of parents of children with autism spectrum disorder in Singapore.

AIMS AND OBJECTIVE: To explore the experiences and support needs of parents of children with recently diagnosed autism spectrum disorder (ASD) in Singapore. BACKGROUND: Raising a child with ASD is challenging for parents, especially in the initial period following the diagnosis. Limited studies have focused on parents' perspectives. DESIGN: A qualitative descriptive design study. METHODS: Thirteen parents were recruited from a developmental and behavioural paediatric outpatient clinic of a tertiary hospital in Singapore from October-December 2018. Adult parents, who were primary caregivers of 2-10-year-old children diagnosed with ASD in the preceding 3 months to 2 years, were recruited. Semi-structured individual face-to-face interviews were conducted based on an interview guide. Thematic analysis was used to analyse the data. Consolidated Criteria for Reporting Qualitative Studies (COREQ) checklist was used for reporting. RESULTS: Common themes were analysed using constant comparative method to generate results. Four themes emerged after 13 interviews: (1) adjusting psychologically, (2) changing lifestyle, (3) contending with hurdles to services and (4) needing informational, tangible and emotional support. CONCLUSIONS: Findings suggested a need for more formal support networks, targeted resource platforms and accessibility of services to help support parents better after receiving a diagnosis of ASD in their child. RELEVANCE TO CLINICAL PRACTICE: Enhancing current healthcare and social policies to improve the provision of standardised and targeted information to parents, establishing formal support networks, facilitating access to childcare services, and involving domestic helpers/nannies as dedicated caregivers and trainers could better support parents.

Television viewing and child cognition in a longitudinal birth cohort in Singapore: the role of maternal factors.

BACKGROUND: Although infant media exposure has received attention for its implications on child development, upstream risk factors contributing to media exposure have rarely been explored. The study aim was to examine the relationship between maternal risk factors, infant television (TV) viewing, and later child cognition. METHODS: We used a prospective population-based birth cohort study, Growing Up in Singapore Towards healthy Outcomes (GUSTO), with 1247 pregnant mothers recruited in their first trimester. We first explored the relationship of infant TV exposure at 12 months and the composite IQ score at 4.5 years, as measured by the Kaufman Brief Intelligence Test, Second Edition (KBIT-2). Multivariable linear regressions were adjusted for maternal education, maternal mental health, child variables, birth parameters, and other relevant confounders. We then examined the associations of maternal risk factors with the amount of daily TV viewing of 12-month-old infants. Path analysis followed, to test a conceptual model designed a priori to test our hypotheses. RESULTS: The average amount of TV viewing at 12 months was 2.0 h/day (SD 1.9). TV viewing in hours per day was a significant exposure variable for composite IQ (ß = - 1.55; 95% CI: - 2.81 to - 0.28) and verbal IQ (ß = - 1.77; 95% CI: - 3.22 to - 0.32) at 4.5 years. Our path analysis demonstrated that lower maternal education and worse maternal mood (standardized ß = - 0.27 and 0.14, respectively, p < 0.01 for both variables) were both risk factors for more media exposure. This path analysis also showed that maternal mood and infant TV strongly mediated the relationship between maternal education and child cognition, with an exceptional model fit (CFI > 0.99, AIC 15249.82, RMSEA < 0.001). CONCLUSION: Infant TV exposure has a negative association with later cognition. Lower maternal education and suboptimal maternal mental health are risk factors for greater television viewing. Paediatricians have a role in considering and addressing early risks that may encourage television viewing.

Screen time exposure and sleep among children with developmental disabilities.

AIM: Children with developmental disabilities are at risk of excessive screen time and are more vulnerable to sleep problems. The aim of this study was to determine the extent of screen time use in children with developmental disabilities and its relationship with sleep duration. METHODS: Consecutive children aged 6-15 years diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth or Fifth Edition (DSM-IV or DSM-5) developmental disabilities were recruited for this study from December 2014 to April 2015. Of those recruited, 87.0% of families gave consent and provided questionnaire information on demographics and child's screen time use and completed the Children's Sleep Habits Questionnaire. RESULTS: Parents of 102 children in a tertiary-care developmental clinic completed the study. The mean age of children was 10 years, 1 month (standard deviation (SD), 22.7 months). The mean daily total screen time exposure was 2 h, 52.7 min (172.7 min, SD 120.8 min), with a median of 150.0 min. The mean amount of sleep per weekday was 8 h, 23.3 min (SD 64.6 min). Linear regression showed that, for every additional 9.17 min of screen time per day, sleep was reduced by 1 min (ß = -0.11, P = 0.04). Older age (ß = -0.64, P = 0.02) and living with a single parent (ß = -69.29, P = 0.003) were also associated with less sleep. CONCLUSIONS: Among children with developmental disabilities, greater daily screen time is associated with lower sleep duration. Older children and those from single-parent families are at risk of lower sleep duration. Clinicians should routinely ask about screen time exposure and sleep habits in order to provide appropriate anticipatory guidance.

An Update on Psychopharmacological Treatment of Autism Spectrum Disorder.

While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD. Appeared originally in Neurotherapeutics 2022; 19:248-262.

Development of oral health resources and a mobile app for caregivers and autistic children through consensus building.

LAY ABSTRACT: Caregivers of autistic children often lack knowledge regarding oral homecare and when and where to see the dentist. To address this need, we developed a series of information on oral health. An autistic child assisted in developing two social stories to showcase a dental visit. A mobile app was developed to deliver the above mentioned. Other features include creation of customised social stories and visual schedule and an inbox to allow dentists to send messages to parents. The developed information and social stories were reviewed by experts and parents. The app also underwent anonymous and independent testing by parents. Overall the information and app were well received by the experts and parents.

Quality of Life and Its Associated Correlates of Parents of Children on the Autism Spectrum in Singapore.

This cross-sectional study aimed to assess Quality of life (QoL) of parents of children on the autism spectrum in Singapore and identify its associated factors. Parents of children (age ≥ 5 years) completed the Quality of Life in Autism scale which measures parental self-rated QoL (higher scores denote greater QoL), and the perceived impact of the child's autism-related behaviors on parents (higher scores denote lesser impact). Information on the child's degree of autism (measured by the Social Responsiveness Scale, second edition [SRS-2]), community and social participation and cognitive and adaptive functioning were also obtained. Participants were 86 parents with mean child age 6.3 years (SD 1.0). Univariate analysis results revealed greater participation in community and social events to be two modifiable factors associated with higher parental QoL. However, these factors were not found to be significant in the multivariate model. Higher autism features (represented by higher parent-rated SRS scores) was associated with a greater perceived impact of the child's behaviors by parents in both univariate and multivariate analyses. Of note, child's cognitive or adaptive skills were not significantly associated with either QoL measure. Equipping parents to handle autism-related behaviors can be useful to reduce their impact on parental QoL. Facilitating community participation for these children may positively influence caregiver QoL as well.

Screen time and social-emotional skills in preschoolers with developmental, behavioural or emotional issues in Singapore.

Introduction: This study aimed to determine patterns of screen viewing time (SVT) in preschool children with developmental, behavioural or emotional (DBE) issues, and to identify its relationship with social-emotional development. Method: This cross-sectional study involved children aged 0-5 years who were referred to a developmental paediatric clinic for DBE issues. Parents completed a screen time questionnaire, and the Devereux Early Childhood Assessment-Clinical (DECA-C) question-naire which assessed the social-emotional competence of the children. Data were analysed using logistic regression, correlational analyses and tests of comparison. Results: Among 225 children (mean age: 32.4 months), mean daily SVT was 138 minutes. More than half (51.1%) of the children had clinical features of language delay, while 26.6% had features suggestive of autism spectrum disorder. Screen time was first introduced at a mean age of 13.8 months, with 32.4% of children previously experiencing higher SVT. Compared to SVT introduction after 1 year of age, SVT in the first 12 months was primarily to facilitate feeding (P<0.05). Children with higher past SVT had poorer attention, more aggression, and increased behavioural concerns. Children with DBE issues have significantly more screen time than same-aged peers. Conclusion: Children with DBE issues are exposed to SVT at a very young age and have significantly more screen time than their peers. It is crucial to guide parents to reduce SVT in early childhood, particularly around mealtimes.

Health practices, behaviours and quality of life of low-income preschoolers: A community-based cross-sectional comparison study in Singapore.

Introduction: Children from low-income (LI) families often suffer from poor health, with sub-optimal health practices. This cross-sectional study examined the differences in health habits and health-related quality of life (HRQoL) of LI preschool children compared to non-low-income preschool peers (PPG). Method: Using data from the social-health Circle of Care-Health Development Screening Programme (CoC-HDSP) in Singapore, 118 LI children and 304 PPG children aged 18 months to 6 years old and their families were recruited from 13 government-funded preschools. Health practices examined included screen time habits, sleep, nutrition, dental health and the children's HRQoL using PedsQL 4.0 Generic Core Scales. Results: Majority of the children were aged 4-6 years in kindergarten 1 and 2. There were more Malay children in the LI than the PPG (61.9% versus [vs] 29.3%, P<0.001). Low-income children were more likely to have lower-educated parents (P<0.001). The completed vaccination rate in the LI group was lower than those in PPG (84.7% vs 98.0%, P<0.001). More in the LI group utilised emergency services for acute illnesses (P<0.05). Fewer LI children had ever visited a dentist (47.4% vs 75.4%, P<0.001), and more LI children consumed sweetened drinks daily (33.3% vs 8.6%, P<0.001). The LI group reported poorer-quality sleep (48.3% vs 27.2%, P<0.001), though both groups exceeded the daily recommended screen viewing duration. The LI group scored higher in the social (mean 92.4±12.2 vs 84.3±15.3, P<0.001) and emotional (mean 85.2±15.1 vs 76.6±17.3, P<0.001) domains of the PedsQL 4.0 when compared to PPG. Conclusion: Low-income children have poorer health practices, receive less preventive paediatric care, and utilise more emergency services for acute illnesses. These findings are important for developing interventions that work towards improving the health of LI children.

2023 clinical practice guidelines on autism spectrum disorder in children and adolescents in Singapore.

Introduction: Autism is a neurodevelopmental condition that is increasing in prevalence worldwide. There has been an exponential increase in autism-related research since 2010, when the first Singapore Clinical Practice Guidelines (CPG) on autism was published. Understanding of autism has since evolved to adopt a lifespan approach beyond that of a childhood condition. The aim of this CPG was to provide an updated set of recommendations for children and adolescents to aid clinical practice for professionals. Method: A multidisciplinary workgroup that comprised representatives from various sectors worked on this CPG. Clinical questions were organised into 10 different sections, each with its own subgroup of members. Seventeen existing international guidelines were evaluated using the Appraisal of Guidelines for REsearch & Evaluation II (AGREE-II) framework, of which 4 met criteria to act as references. Literature review across multiple databases was conducted between January 2011 to 2023; Grading of Recommendations, Assessment, Development and Evaluation (GRADE-like) methodology was used to synthesise evidence. Recommendation statements were derived, following Delphi-style consensus surveys among the workgroup. The draft guidelines underwent external review and public consultation before being formalised. Results: Recommendation and good practice statements pertaining to care of children and adolescents on the autism spectrum across 10 different sections were developed. Evidence matrices complement these recommendations and detail relevant evidence behind each recommendation statement. Conclusion: It is intended for these guidelines to promote effective management and healthcare services for children and adolescents on the autism spectrum, by reinforcing good and evidence-based clinical practice within our national context.

Meta-analysis of the Modified Checklist for Autism in Toddlers, Revised/Follow-up for Screening.

CONTEXT: The Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F) is used worldwide to screen for autism spectrum disorder (ASD). OBJECTIVE: To calculate psychometric properties of the M-CHAT-R/F for subsequent diagnosis of ASD. DATA SOURCES: Systematic searches of Medline, Embase, SCOPUS, and Trip Pro databases from January 2014 to November 2021. STUDY SELECTION: Studies were included if they (1) used the M-CHAT-R/F (2) applied standard scoring protocol, (3) used a diagnostic assessment for ASD, and (4) reported at least 1 psychometric property of the M-CHAT-R/F. DATA EXTRACTION: Two independent reviewers completed screening, full-text review, data extraction, and quality assessment, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A random-effects model was used to derive pooled estimates and assess for between-study heterogeneity. RESULTS: Of 667 studies identified, 15 with 18 distinct samples from 10 countries (49 841 children) were used in the meta-analysis. Pooled positive predictive value (PPV), was 57.7% (95% confidence interval [CI] 48.6-66.8, τ2 = 0.031). PPV was higher among high-risk (75.6% [95% CI 66.0-85.2]) than low-risk samples (51.2% [95% CI 43.0-59.5]). Pooled negative predictive value was 72.5% (95% CI 62.5-82.4 τ2 = 0.031), sensitivity was 82.6% (95% CI 76.2-88.9) and specificity 45.7% (95% CI 25.0-66.4). LIMITATIONS: Negative predictive value, sensitivity, and specificity were calculated based on small sample sizes because of limited or no evaluation of screen-negative children. CONCLUSIONS: These results support use of the M-CHAT-R/F as a screening tool for ASD. Caregiver counseling regarding likelihood of an ASD diagnosis after positive screen should acknowledge the moderate PPV.

Validity and feasibility of using the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) in primary care clinics in Singapore.

LAY ABSTRACT: Systematic screening for autism in early childhood has been suggested to improve eventual outcomes by facilitating earlier diagnosis and access to intervention. However, clinical implementation of screening has to take into account effectiveness and feasibility of use within a healthcare setting for accurate diagnosis of autism. In Singapore, autism screening using a structured screening tool is not currently employed as a part of routine well-child visits for children in primary care clinics. In this study, 5336 children (aged 17-20 months) were screened for autism using the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) during their 18-month well-child visit in seven primary care clinics. Screening and follow-up interviews were administered by nursing staff at each clinic. Children screened positive and a portion of those screened negative then underwent diagnostic assessments to determine whether they met the diagnostic criteria for autism. In total, 113 (2.1%) were screened positive, of which 54 (1.0%) met the criteria for autism. Children who screened positive and received a diagnosis accessed autism-specific intervention at an average age of 22 months. Nurses and physicians rated the acceptability and practicality of the M-CHAT-R/F highly. Therefore, the M-CHAT-R/F questionnaire was an effective and feasible tool for autism screening among 18-month-old children in this study. Future studies will be designed to determine the optimal age of screening and role of repeated screening in Singapore, as well as to better understand any potential improved outcomes nationwide compared with pre-implementation of autism screening.

Fragile X Syndrome and Fetal Alcohol Syndrome: Occurrence of Dual Diagnosis in a Set of Triplets.

BACKGROUND: Fragile X syndrome (FXS) and fetal alcohol syndrome disorders are both common causes of intellectual disability in children. When both conditions are present in the same individual, the resultant phenotype may make identification of clinical issues and management challenging. CASE PRESENTATION: In this case report, we present a case of triplets who had significant in utero alcohol exposure; 2 of whom also have FXS and the other not having the fragile X mutation. The siblings with FXS have subtle differences in the physical phenotype compared with the other one, who has prominent features of partial fetal alcohol syndrome instead. However, all 3 siblings have intellectual impairment (although this is more severe in the 2 with FXS), meet diagnostic criteria for autism spectrum disorder, and present with severe behavioral challenges. The clinical presentation of the 2 siblings with FXS is much more severe as compared to a child with FXS alone, and this is likely due to the additive effect of in utero alcohol exposure and environmental factors. We discuss the combination of these 2 pathologies and how this can affect the overall clinical presentation. CONCLUSION: In the management of children with FXS, evaluation for other risk factors that can have neurobehavioral sequelae is important, and these can affect clinical presentation and prognosis.

Case report: Transient symptoms of autism spectrum disorder in a 2-year-old boy.

Though early ASD diagnosis is highly stable, this case report describes a rare situation in which symptoms resolved without intervention over a 4 month period. We do not recommend delaying diagnosis in symptomatic children who meet criteria but when major behavioral changes are reported after diagnosis, reevaluation may be beneficial.

Clinical implications of somatic allele expansion in female FMR1 premutation carriers.

Carriers of a premutation allele (PM) in the FMR1 gene are at risk of developing a number of Fragile X premutation asssociated disorders (FXPAC), including Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-associated neuropsychiatric disorders (FXAND). We have recently reported somatic CGG allele expansion in female PM; however, its clinical significance remains unclear. The aim of this study was to examine the potential clinical association between somatic FMR1 allele instability and PM associated disorders. Participants comprised of 424 female PM carriers age 0.3- 90 years. FMR1 molecular measures and clinical information on the presence of medical conditions, were determined for all subjects for primary analysis. Two sub-groups of participants (age ≥ 25, N = 377 and age ≥ 50, N = 134) were used in the analysis related to presence of FXPOI and FXTAS, respectively. Among all participants (N = 424), the degree of instability (expansion) was significantly higher (median 2.5 vs 2.0, P = 0.026) in participants with a diagnosis of attention deficit hyperactivity disorder (ADHD) compared to those without. FMR1 mRNA expression was significantly higher in subjects with any psychiatric disorder diagnosis (P = 0.0017); specifically, in those with ADHD (P = 0.009), and with depression (P = 0.025). Somatic FMR1 expansion was associated with the presence of ADHD in female PM and FMR1 mRNA levels were associated with the presence of mental health disorders. The findings of our research are innovative as they suggest a potential role of the CGG expansion in the clinical phenotype of PM and may potentially guide clinical prognosis and management.