1. Aung MT, K MB, Feinberg JI, J FD, J DM, Mukherjee B, Loch-Caruso R, Ladd-Acosta C, Volk HE, Croen LA, Hertz-Picciotto I, Newschaffer CJ, Fallin MD. Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI). Epigenetics. 2022; 17(3): 253-68.

The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead-associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese-associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.

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2. Baker E, Stavropoulos KKM, Baker BL, Blacher J. Daily living skills in adolescents with autism spectrum disorder: Implications for intervention and independence. Research in autism spectrum disorders. 2021; 83.

BACKGROUND: Challenges in adaptive behaviors are present in individuals with autism spectrum disorder (ASD), while variation in IQ, social skills, and comorbidities are possible influences on adaptive behaviors. However, adaptive behaviors do not consistently map onto cognitive abilities in ASD, as high IQ is not protective against challenges in adaptive behaviors. Additionally, individuals with both ASD and elevated levels of externalizing problem behaviors experience even worse adaptive behaviors. Identifying factors that contribute to the variance in adaptive behaviors, particularly daily living skills (DLS), may inform strategies to improve adaptive behaviors necessary for independence in adulthood. METHOD: Adolescents with typical cognitive development (TD, n=84), intellectual disability (ID, n=30), or ASD (n=45) were included in this study to examine group differences in adaptive behaviors, identify relations between IQ and DLS, and determine factors that contribute to variance in DLS at youth age 13. The Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II) was used to measure adaptive behaviors. RESULTS: All domains of adaptive behavior were significantly higher in TD groups compared to ASD and ID youth. Significant positive correlations were observed between IQ and DLS in the ASD and ID groups. In the ASD youth group, higher externalizing behavior problems explained the most variance in DLS. CONCLUSIONS: DLS are below age-expected levels in young adolescents with ASD, in part because of the higher externalizing behavior problems in this group. Incorporating adaptive skills training and behavior management strategies into current interventions may serve to prepare adolescents and families for the transition to adulthood.

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3. Barhoun P, Fuelscher I, Do M, He JL, Bekkali S, Cerins A, Youssef GJ, Williams J, Enticott PG, Hyde C. Mental rotation performance in young adults with and without developmental coordination disorder. Human movement science. 2021; 77: 102787.

While there have been consistent behavioural reports of atypical hand rotation task (HRT) performance in adults with developmental coordination disorder (DCD), this study aimed to clarify whether this deficit could be attributed to specific difficulties in motor imagery (MI), as opposed to broad deficits in general mental rotation. Participants were 57 young adults aged 18-30 years with (n = 22) and without DCD (n = 35). Participants were compared on the HRT, a measure of MI, and the letter number rotation task (LNRT), a common visual imagery task. Only participants whose behavioural performance on the HRT suggested use of a MI strategy were included in group comparisons. Young adults with DCD were significantly less efficient compared to controls when completing the HRT yet showed comparable performance on the LNRT relative to adults with typical motor ability. Our data are consistent with the view that atypical HRT performance in adults with DCD is likely to be attributed to specific difficulties engaging in MI, as opposed to deficits in general mental rotation. Based on the theory that MI provides insight into the integrity of internal action representations, these findings offer further support for the internal modelling deficit hypothesis of DCD.

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4. Bölte S, Lawson WB, Marschik PB, Girdler S. Reconciling the seemingly irreconcilable: The WHO’s ICF system integrates biological and psychosocial environmental determinants of autism and ADHD: The International Classification of Functioning (ICF) allows to model opposed biomedical and neurodiverse views of autism and ADHD within one framework. BioEssays : news and reviews in molecular, cellular and developmental biology. 2021; 43(9): e2000254.

Neurodevelopmental disorders (NDDs), such as autism and ADHD, are behaviorally defined adaptive functioning difficulties arising from variations, alterations and atypical maturation of the brain. While it is widely agreed that NDDs are complex conditions with their presentation and functional impact underpinned by diverse genetic and environmental factors, contemporary and polarizing debate has focused on the appropriateness of the biomedical as opposed to the neurodiverse paradigm in framing conceptions of these conditions. Despite being largely overlooked by both research and practice, the International Classification of Functioning Disability and Health (ICF) endorsed by the World Health Organization in 2001 views functioning dynamically, offering a framework for investigating, assessing and treating NDDs holistically. Exemplified by autism and ADHD, we argue that the ICF provides not only a multitude of opportunities in accounting for the environmental determinants in researching and clinically managing NDDs, but opportunities for harmonizing the seemingly irreconcilable biomedical and neurodiverse paradigms. Also see the video abstract here: https://youtu.be/YwuWPDUOs5k.

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5. Coussens M, Vitse F, Desoete A, Vanderstraeten G, Van Waelvelde H, Van de Velde D. Participation of young children with developmental disabilities: parental needs and strategies, a qualitative thematic analysis. BMJ open. 2021; 11(4): e042732.

OBJECTIVES: Participation refers to a person’s involvement in activities and roles that provide interaction with others as well as engagement in family and community activities. Young children with developmental disabilities (DD) such as attention deficit hyperactive disorder, autism spectrum disorder and developmental coordination disorder are limited in their participation compared with their typically developing peers. This study aimed to obtain information regarding parental needs and strategies used to enable their child’s participation. DESIGN: A thematic inductive approach with in-depth interviews was used to explore parental experiences. Eleven women and two men, between 30 and 40 years of age, who had a child (4-9 years old) with a DD diagnosis based on Diagnostic and Statistical Manual of Mental Disorders criteria, participated in semistructured interviews. RESULTS: Two central themes emerged: parental needs and parental strategies used to enable their child’s participation. Parental needs were the following: increasing awareness, ameliorating parental burden, providing tailored interventions and supporting parents in finding suitable leisure activities. Parental strategies aimed at increasing their child’s resiliency, attaining maximal fit between activity requirements and child capacity, and creating inclusive opportunities and awareness. CONCLUSIONS: Understanding what families’ needs are and how families use and integrate strategies within the context of their daily lives provides practitioners with insights needed to support families’ resiliency in promoting their children’s participation. The results have implications for professionals as this information can be used to inform, refine, or tailor participation-based and family-centred services.

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6. Devito LG, Healy L, Mohammed S, Guillemot F, Dias C. Generation of an iPSC line (CRICKi001-A) from an individual with a germline SMARCA4 missense mutation and autism spectrum disorder. Stem cell research. 2021; 53: 102304.

Germline missense mutations in the BAF swi/snf chromatin remodeling subunit SMARCA4 are associated with neurodevelopmental disorders, including Coffin Siris Syndrome (CSS). Here, we generated an induced pluripotent stem cell line from a male patient with atypical CSS features and a de novo heterozygous missense mutation in the SMARCA4 gene (c.3607C>T, p.(Arg1203Cys)). Hair root derived keratinocytes were reprogrammed using non-integrative Sendai virus vector delivery of pluripotency factors. iPSCs generated display normal morphology and molecular karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

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7. Dovgan KN, Villanti KM. The Prevalence of Broad Autism Phenotype in Young Adults: The Roles of Genetic Relationship to Autism, Gender, and Academic Major. The Journal of genetic psychology. 2021; 182(3): 174-81.

Subclinical levels of autism traits are known as the Broad Autism Phenotype (BAP) and include a rigid personality, aloof personality, and pragmatic language difficulties. Genetic relatives of children with autism spectrum disorder (ASD), males, and those in math- or science-oriented careers may be more likely to exhibit BAP. This study examined the prevalence of BAP in young adults to assess the influence of genetic relationship to ASD, gender, and academic field. Online self-report data from 170 undergraduate college students included the Broad Autism Phenotype Questionnaire (BAPQ), information about genetic relationship to ASD, and demographic information. Results showed no relationship between BAP and level of shared ASD genes, gender, or academic major. However, 25.3% of our college-aged sample met BAP cutoffs, compared to previous estimates of only 5-9% of adult parents of neurotypical children and 14-23% of parents of children with ASD. These findings expand our understanding of subclinical autistic traits in young adults. This research highlights the need to investigate community-based samples of various age groups when estimating the prevalence of BAP to better-understand the extent to which these personality characteristics are present in the general population.

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8. Ebrahim MT, Alothman AA. Resilience and social support as predictors of post-traumatic growth in mothers of children with autism spectrum disorder in Saudi Arabia. Research in developmental disabilities. 2021; 113: 103943.

BACKGROUND: There are few studies about the role of resilience and social support in post-traumatic growth (PTG) in parents of children with autism spectrum disorder (ASD). AIM: This study examined the relationship between social support, resilience, and PTG and the predictive role of resilience and social support related to PTG in Saudi Arabian mothers. METHODS AND PROCEDURES: A survey-based quantitative study was conducted in 88 mothers aged 18-46 years (M = 33.5; SD = 8.02) who had a child with ASD. They were sampled from nine day care centers in Riyadh and the Central-Eastern-Southern region. OUTCOMES AND RESULTS: The findings showed a significant positive correlation between perceived social support, resilience, and PTG, and revealed that Resilience-competence was the only significant predictor of PTG-personal strength, appreciation of life, spiritual change new possibilities, and total PTG, while positive acceptance of change was a significant predictor of PTG-relating to others. Moreover, social support from friends and significant others were significant predictors of PTG-total. CONCLUSIONS AND IMPLICATIONS: We found that, for mothers of a child with ASD in Saudi Arabia, the biggest factors predicting post-traumatic growth were a notion of personal competence and social support from friends. Intervention is suggested to lower the risk of trauma.

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9. Espenhahn S, Godfrey KJ, Kaur S, Ross M, Nath N, Dmitrieva O, McMorris C, Cortese F, Wright C, Murias K, Dewey D, Protzner AB, McCrimmon A, Bray S, Harris AD. Tactile cortical responses and association with tactile reactivity in young children on the autism spectrum. Molecular autism. 2021; 12(1): 26.

BACKGROUND: Unusual behavioral reactions to sensory stimuli are frequently reported in individuals on the autism spectrum (AS). Despite the early emergence of sensory features (< age 3) and their potential impact on development and quality of life, little is known about the neural mechanisms underlying sensory reactivity in early childhood autism. METHODS: Here, we used electroencephalography (EEG) to investigate tactile cortical processing in young children aged 3-6 years with autism and in neurotypical (NT) children. Scalp EEG was recorded from 33 children with autism, including those with low cognitive and/or verbal abilities, and 45 age- and sex-matched NT children during passive tactile fingertip stimulation. We compared properties of early and later somatosensory-evoked potentials (SEPs) and their adaptation with repetitive stimulation between autistic and NT children and assessed whether these neural measures are linked to "real-world" parent-reported tactile reactivity. RESULTS: As expected, we found elevated tactile reactivity in children on the autism spectrum. Our findings indicated no differences in amplitude or latency of early and mid-latency somatosensory-evoked potentials (P50, N80, P100), nor adaptation between autistic and NT children. However, latency of later processing of tactile information (N140) was shorter in young children with autism compared to NT children, suggesting faster processing speed in young autistic children. Further, correlational analyses and exploratory analyses using tactile reactivity as a grouping variable found that enhanced early neural responses were associated with greater tactile reactivity in autism. LIMITATIONS: The relatively small sample size and the inclusion of a broad range of autistic children (e.g., with low cognitive and/or verbal abilities) may have limited our power to detect subtle group differences and associations. Hence, replications are needed to verify these results. CONCLUSIONS: Our findings suggest that electrophysiological somatosensory cortex processing measures may be indices of "real-world" tactile reactivity in early childhood autism. Together, these findings advance our understanding of the neurophysiological mechanisms underlying tactile reactivity in early childhood autism and, in the clinical context, may have therapeutic implications.

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10. Gakenheimer-Smith L, Meyers L, Lundahl D, Menon SC, Bunch TJ, Sawyer BL, Tristani-Firouzi M, Etheridge SP. Expanding the phenotype of CACNA1C mutation disorders. Molecular genetics & genomic medicine. 2021; 9(6): e1673.

BACKGROUND: Pathogenic variants in the L-type Ca(2+) channel gene CACNA1C cause a multi-system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac-only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra-cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations. METHODS: A four-generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great-uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant. RESULTS: In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome. CONCLUSION: Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L-type Ca(2+) channel.

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11. Grahame V, Dixon L, Fletcher-Watson S, Garland D, Glod M, Goodwin J, Grayson Z, Heron S, Honey E, Iversen R, Kasim AS, Kernohan A, Kharatikoopaei E, Le Couteur A, Mackie L, Mathias A, Probert H, Riby D, Rob P, Rogan L, Thompson S, Vale L, Walls E, Webb EI, Weetman C, Wolstenhulme F, Wood R, Rodgers J. A clinical and cost-effectiveness trial of a parent group intervention to manage challenging restricted and repetitive behaviours in young children with autism spectrum disorder: study protocol for a randomised controlled trial. Trials. 2021; 22(1): 240.

BACKGROUND: Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child’s challenging restricted repetitive behaviours. METHODS: The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) (n = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3-9 years 11 months with a diagnosis of autism. All analyses will be done under intention-to-treat principle. The primary outcome at 24 weeks will use generalised estimating equation (GEE) to compare proportion of children with improved RRB between the MRB group and the LAA group. The GEE model will account for the clustering of children by parent groups using exchangeable working correlation. All secondary outcomes will be analysed in a similar way using appropriate distribution and link function. The economic evaluation will be conducted from the perspective of both NHS costs and family access to local community services. A ‘within trial’ cost-effectiveness analysis with results reported as the incremental cost per additional child achieving at least the target improvement in CGI-I scale at 24 weeks. DISCUSSION: This is an efficacy trial to investigate the clinical and cost-effectiveness of a parent group based intervention designed to help parents understand and manage their child’s challenging RRB. If found to be effective, this intervention has the potential to improve the well-being of children and their families, reduce parental stress, greatly enhance community participation and potential for learning, and improve longer-term outcomes. TRIAL REGISTRATION: Trial ID: ISRCTN15550611 Date registered: 07/08/2018. Sponsor and Monitor: Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust R&D Manager Lyndsey Dixon, Address: St Nicholas Hospital, Jubliee Road, Gosforth, Newcastle upon Tyne NE3 3XT, lyndsey.dixon@cntw.nhs.uk , Tel: 0191 246 7222.

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12. Jequier Gygax M, Maillard AM, Favre J. Could Gait Biomechanics Become a Marker of Atypical Neuronal Circuitry in Human Development?-The Example of Autism Spectrum Disorder. Frontiers in bioengineering and biotechnology. 2021; 9: 624522.

This perspective paper presents converging recent knowledge in neurosciences (motor neurophysiology, neuroimaging and neuro cognition) and biomechanics to outline the relationships between maturing neuronal network, behavior, and gait in human development. Autism Spectrum Disorder (ASD) represents a particularly relevant neurodevelopmental disorder (NDD) to study these convergences, as an early life condition presenting with sensorimotor and social behavioral alterations. ASD diagnosis relies solely on behavioral criteria. The absence of biological marker in ASD is a main challenge, and hampers correlations between behavioral development and standardized data such as brain structure alterations, brain connectivity, or genetic profile. Gait, as a way to study motor system development, represents a well-studied, early life ability that can be characterized through standardized biomechanical analysis. Therefore, developmental gait biomechanics might appear as a possible motor phenotype and biomarker, solid enough to be correlated to neuronal network maturation, in normal and atypical developmental trajectories-like in ASD.

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13. Li YF, Scerif F, Picker SR, Stone TJ, Pickles JC, Moulding DA, Avery A, Virasami A, Fairchild AR, Tisdall M, Harkness W, Cross JH, Hargrave D, Guillemot F, Paine SM, Yasin SA, Jacques TS. Identifying cellular signalling molecules in developmental disorders of the brain: Evidence from focal cortical dysplasia and tuberous sclerosis. Neuropathology and applied neurobiology. 2021; 47(6): 781-95.

AIMS: We understand little of the pathogenesis of developmental cortical lesions, because we understand little of the diversity of the cell types that contribute to the diseases or how those cells interact. We tested the hypothesis that cellular diversity and cell-cell interactions play an important role in these disorders by investigating the signalling molecules in the commonest cortical malformations that lead to childhood epilepsy, focal cortical dysplasia (FCD) and tuberous sclerosis (TS). METHODS: Transcriptional profiling clustered cases into molecularly distinct groups. Using gene expression data, we identified the secretory signalling molecules in FCD/TS and characterised the cell types expressing these molecules. We developed a functional model using organotypic cultures. RESULTS: We identified 113 up-regulated secretory molecules in FCDIIB/TS. The top 12 differentially expressed genes (DEGs) were validated by immunohistochemistry. This highlighted two molecules, Chitinase 3-like protein 1 (CHI3L1) and C-C motif chemokine ligand 2 (CCL2) (MCP1) that were expressed in a unique population of small cells in close proximity to balloon cells (BC). We then characterised these cells and developed a functional model in organotypic slice cultures. We found that the number of CHI3L1 and CCL2 expressing cells decreased following inhibition of mTOR, the main aberrant signalling pathway in TS and FCD. CONCLUSIONS: Our findings highlight previously uncharacterised small cell populations in FCD and TS which express specific signalling molecules. These findings indicate a new level of diversity and cellular interactions in cortical malformations and provide a generalisable approach to understanding cell-cell interactions and cellular heterogeneity in developmental neuropathology.

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14. Ma J, Wu J, Li H, Wang J, Han J, Zhang R. Association Between Essential Metal Elements and the Risk of Autism in Chinese Han Population. Biological trace element research. 2022; 200(2): 505-15.

Essential metal elements (EMEs) have essential roles in neurological development and maintenance of human homeostasis. We performed a case-control study to explore association between the risk of autism spectrum disorder (ASD) and the 11 EMEs [Calcium (Ca), potassium (K), magnesium (Mg), sodium (Na), manganese (Mn), selenium (Se), cobalt (Co), Molybdenum (Mo), copper (Cu), zinc (Zn), and iron (Fe)] in serum. Ninety-two autistic subjects (cases) and age-sex-matched healthy subjects (controls = 91) from Beijing, China were recruited. In addition, totally 109 mothers of recruited children participated in this study. ICP-AES and ICP-MS were applied to determine the concentration of 11 EMEs in serum. The concentrations of Ca, K, and Mg were significantly higher in the cases than in the controls (OR [95% CI]: 1.031 [1.006-1.058] for Ca; 1.081 [1.046-1.118] for K; 1.161 [1.012-1.331] for Mg), while the concentrations of Zn and Cu were significantly lower (0.997 [0.995-0.999] for Cu; 0.996 [0.992-1.000] for Zn). Clear dose-response relationships between EMEs concentrations and the risk of ASD, as well as the correlation between EME concentrations and the severity of ASD were observed for most of the above EMEs. Six and seven specific correlated pairs between mothers and children were found in the cases and controls separately. The overall profiles of the EMEs were changed in the cases as compared to the controls. This study suggested that the higher levels of Ca, K, and Mg and lower levels of Zn and Cu may be associated with an elevated risk of ASD.

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15. Sabbagh HJ, Al-Jabri BA, Alsulami MA, Hashem LA, Aljubour AA, Alamoudi RA. Prevalence and characteristics of autistic children attending autism centres in 2 major cities in Saudi Arabia: A cross-sectional study. Saudi medical journal. 2021; 42(4): 419-27.

OBJECTIVES: To assess the prevalence and characteristics of Autism Spectrum Disorder (ASD)-affected children attending autistic centers in 2 major cities in Saudi Arabia. METHODS: A cross-sectional study, including ASD centers and schools (37 centers) in Makkah and Jeddah, Saudi Arabia was conducted between January and March 2020. Data were collected from records and parents of children with ASD using a questionnaire on sociodemographic, family history, consanguinity, severity, and maternal risk factors. RESULTS: All centers in Makkah and Jeddah participated, with a total of 1,023 ASD children. The prevalence of ASD was 2.618 per 1,000 children for Jeddah, 3.68 per 1,000 children for Makkah and 2.81 per 1,000 children for both Jeddah and Makkah. There was no statistically significant relationship between the severity of ASD and sociodemographic, family and maternal risk factors. However, there was statistically significant relationship between severe ASD and ASD family history (p=0.029, OR: 3.46 and 95% CI 1.14 to 10.5). CONCLUSIONS: The prevalence of ASD in Makkah and Jeddah was lower than the global prevalence of ASD. Individuals with a family history of ASD were more likely to have more severe ASD.

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16. Spector E, Behlmann A, Kronquist K, Rose NC, Lyon E, Reddi HV. Laboratory testing for fragile X, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics. 2021; 23(5): 799-812.

Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Pathogenic variants in the FMR1 gene are associated with fragile X syndrome, fragile X-associated tremor ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). This document provides updated information regarding FMR1 pathogenic variants, including prevalence, genotype-phenotype correlations, and variant nomenclature. Methodological considerations are provided for Southern blot analysis and polymerase chain reaction (PCR) amplification of FMR1, including triplet repeat-primed and methylation-specific PCR.The American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has the mission of maintaining high technical standards for the performance and interpretation of genetic tests. In part, this is accomplished by the publication of the document ACMG Technical Standards for Clinical Genetics Laboratories, which is now maintained online ( http://www.acmg.net ). This subcommittee also reviews the outcome of national proficiency testing in the genetics area and may choose to focus on specific diseases or methodologies in response to those results. Accordingly, the subcommittee selected fragile X syndrome to be the first topic in a series of supplemental sections, recognizing that it is one of the most frequently ordered genetic tests and that it has many alternative methods with different strengths and weaknesses. This document is the fourth update to the original standards and guidelines for fragile X testing that were published in 2001, with revisions in 2005 and 2013, respectively.This versionClarifies the clinical features associated with different FMRI variants (Section 2.3)Discusses important reporting considerations (Section 3.3.1.3)Provides updates on technology (Section 4.1).

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