{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:44:16Z","timestamp":1784825056431,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T00:00:00Z","timestamp":1671235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["HD036071"],"award-info":[{"award-number":["HD036071"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["P50 HD103526"],"award-info":[{"award-number":["P50 HD103526"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MIND Institute Intellectual and Developmental Disabilities Research Center","award":["HD036071"],"award-info":[{"award-number":["HD036071"]}]},{"name":"MIND Institute Intellectual and Developmental Disabilities Research Center","award":["P50 HD103526"],"award-info":[{"award-number":["P50 HD103526"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: The fragile X premutation carrier state (PM) (55\u2013200 CGG repeats in the fragile X messenger ribonucleoprotein 1, FMR1 gene) is associated with several conditions, including fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor ataxia (FXTAS), with current literature largely primarily investigating older PM individuals. The aim of this study was to identify the prevalence of fragile X-associated neurodevelopmental disorders (FXAND) in a sample of young PM individuals. Methods: This was a retrospective study conducted through a medical record review of PM individuals who were seen either for clinical concerns (probands, 45.9%) or identified through the cascade testing (non-probands, 54.1%) of an affected sibling with fragile X syndrome. Information on the presence of autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, long-term psychiatric medication intake, and cognitive function, based on standardized assessments, was obtained. Molecular data, including CGG repeat number and FMR1 mRNA levels, were also available for a subset of participants. Analysis included descriptive statistics and a test of comparison to describe the clinical profile of PM individuals pertinent to FXAND. Results: Participants included 61 individuals (52 males and 9 females) aged 7.8 to 20.0 years (mean 12.6 \u00b1 3.4) with a mean full-scale IQ of 90.9 \u00b1 22.7. The majority (N = 52; 85.2%) had at least one mental health disorder, with anxiety being the most common (82.0% of subjects), followed by ADHD (66.5%), and ASD (32.8%). Twenty-seven (87.1%) of non-probands also had at least one mental health condition, with probands having lower cognitive and adaptive skills than non-probands. ASD was present in 20 participants (17\/52 males and 3\/9 females; 15 probands) with significantly lower FSIQ in those with ASD (mean 73.5 vs. 98.0, p &lt; 0.001). Participants with ASD had a higher number of long-term medications compared to those without (2.32 vs. 1.3, p = 0.002). Conclusions: Our findings indicate a high rate of FXAND diagnoses within a cohort of young PM individuals, including those identified via cascade testing, although this was not a population sample. An awareness of the entity of FXAND and the early recognition of the symptoms of associated conditions may facilitate timely and appropriate care for PM individuals.<\/jats:p>","DOI":"10.3390\/genes13122399","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T06:58:29Z","timestamp":1671433109000},"page":"2399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Fragile X-Associated Neuropsychiatric Disorders (FXAND) in Young Fragile X Premutation Carriers"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-1248","authenticated-orcid":false,"given":"Ramkumar","family":"Aishworiya","sequence":"first","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA"},{"name":"Khoo Teck Puat-National University Children\u2019s Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore"},{"name":"Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2137-5405","authenticated-orcid":false,"given":"Dragana","family":"Protic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5136-7353","authenticated-orcid":false,"given":"Si Jie","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California Davis, 4610 X St, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4674-7244","authenticated-orcid":false,"given":"Andrea","family":"Schneider","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA"},{"name":"Department of Pediatrics, School of Medicine, University of California Davis, 4610 X St, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6388-9180","authenticated-orcid":false,"given":"Flora","family":"Tassone","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA"},{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, 4610 X St, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-8448","authenticated-orcid":false,"given":"Randi","family":"Hagerman","sequence":"additional","affiliation":[{"name":"Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA"},{"name":"Department of Pediatrics, School of Medicine, University of California Davis, 4610 X St, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17065","DOI":"10.1038\/nrdp.2017.65","article-title":"Fragile X syndrome","volume":"3","author":"Hagerman","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/gm401","article-title":"FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States","volume":"4","author":"Tassone","year":"2012","journal-title":"Genome Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"190","DOI":"10.25100\/cm.v45i4.1810","article-title":"Fragile X syndrome","volume":"45","author":"Saldarriaga","year":"2014","journal-title":"Colomb. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4314","DOI":"10.1172\/JCI63141","article-title":"Fragile X syndrome: Causes, diagnosis, mechanisms, and therapeutics","volume":"122","author":"Bagni","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hagerman, R.J.H., and Paul, J. (2020). Fragile X Syndrome and Premutation Disorders, Mac Keith Press.","DOI":"10.1002\/9781119432692.ch28"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/ajmg.1320380221","article-title":"Heterozygous fragile X female: Historical, physical, cognitive, and cytogenetic features","volume":"38","author":"Cronister","year":"1991","journal-title":"Am. J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1093\/humrep\/deh635","article-title":"Association of FMR1 repeat size with ovarian dysfunction","volume":"20","author":"Sullivan","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1212\/WNL.57.1.127","article-title":"Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X","volume":"57","author":"Hagerman","year":"2001","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1086\/374321","article-title":"Fragile X premutation tremor\/ataxia syndrome: Molecular, clinical, and neuroimaging correlates","volume":"72","author":"Jacquemont","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1001\/jama.291.4.460","article-title":"Penetrance of the fragile X-associated tremor\/ataxia syndrome in a premutation carrier population","volume":"291","author":"Jacquemont","year":"2004","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/nrneurol.2016.82","article-title":"Fragile X-associated tremor\/ataxia syndrome\u2014Features, mechanisms and management","volume":"12","author":"Hagerman","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1086\/302720","article-title":"Elevated levels of FMR1 mRNA in carrier males: A new mechanism of involvement in the fragile-X syndrome","volume":"66","author":"Tassone","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"564","DOI":"10.3389\/fpsyt.2018.00564","article-title":"Fragile X-Associated Neuropsychiatric Disorders (FXAND)","volume":"9","author":"Hagerman","year":"2018","journal-title":"Front. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/ajmg.b.30786","article-title":"Mood and anxiety disorders in females with the FMR1 premutation","volume":"150","author":"Roberts","year":"2009","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.biopsych.2015.07.015","article-title":"Trajectory and Predictors of Depression and Anxiety Disorders in Mothers with the FMR1 Premutation","volume":"79","author":"Roberts","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1002\/ajmg.1320510416","article-title":"Emotional and neurocognitive deficits in fragile X","volume":"51","author":"Sobesky","year":"1994","journal-title":"Am. J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1002\/ajmg.a.32439","article-title":"Co-occurring conditions associated with FMR1 gene variations: Findings from a national parent survey","volume":"146","author":"Bailey","year":"2008","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S137","DOI":"10.1097\/00004703-200604002-00012","article-title":"Autism spectrum disorders and attention-deficit\/hyperactivity disorder in boys with the fragile X premutation","volume":"27","author":"Farzin","year":"2006","journal-title":"J. Dev. Behav. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1007\/s10803-006-0205-z","article-title":"Autism spectrum phenotype in males and females with fragile X full mutation and premutation","volume":"37","author":"Clifford","year":"2007","journal-title":"J. Autism. Dev. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s00439-011-1106-6","article-title":"Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder","volume":"131","author":"Chonchaiya","year":"2012","journal-title":"Hum. Genet."},{"key":"ref_21","unstructured":"Lord, C., Rutter, M., DiLavore, P., Risi, S., Gotham, K., and Bishop, S. (2012). Autism Diagnostic Observation Schedule, Western Psychological Services. [2nd ed.]. Manual (Part 1): Modules 1\u20134."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wechsler, D. (1999). Wechsler Abbreviated Scale of Intelligence, Psychological Corporation.","DOI":"10.1037\/t15170-000"},{"key":"ref_23","unstructured":"Roid, G.H., and Pomplun, M. (2012). The Stanford-Binet Intelligence Scales, The Guilford Press."},{"key":"ref_24","unstructured":"Wechsler, D. (1955). Wechsler adult intelligence scale. Arch. Clin. Neuropsychol."},{"key":"ref_25","unstructured":"Sparrow, S.S., Balla, D.A., Cicchetti, D.V., and Doll, E.A. (1984). Vineland Adaptive Behavior Scales Interview Edition Expanded Form Manual, American Guidance Services, Inc."},{"key":"ref_26","unstructured":"First, M.B., Gibbon, M., Spitzer, R.L., Williams, J.B., and Benjamin, L.S. (1997). Structured Clinical Interview for DSM-IV\u00ae Axis II Personality Disorders SCID-II., American Psychiatric Pub."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2353\/jmoldx.2008.070073","article-title":"A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations","volume":"10","author":"Tassone","year":"2008","journal-title":"J. Mol. Diagn."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1373\/clinchem.2009.136101","article-title":"A novel FMR1 PCR method for the routine detection of low abundance expanded alleles and full mutations in fragile X syndrome","volume":"56","author":"Sah","year":"2010","journal-title":"Clin. Chem."},{"key":"ref_29","unstructured":"Corp, I. (2011). IBM SPSS Statistics for Windows, IBM Corp.. Version 22.0."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"123","DOI":"10.5582\/irdr.2015.01029","article-title":"Anxiety disorders in fragile X premutation carriers: Preliminary characterization of probands and non-probands","volume":"4","author":"Cordeiro","year":"2015","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.chc.2005.06.003","article-title":"The developmental epidemiology of anxiety disorders: Phenomenology, prevalence, and comorbidity","volume":"14","author":"Costello","year":"2005","journal-title":"Child Adolesc. Psychiatr. Clin. N. Am."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.su7102a1","article-title":"Mental Health Surveillance Among Children\u2014United States, 2013\u20132019","volume":"71","author":"Bitsko","year":"2022","journal-title":"MMWR Suppl."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.jpeds.2018.09.021","article-title":"Prevalence and Treatment of Depression, Anxiety, and Conduct Problems in US Children","volume":"206","author":"Ghandour","year":"2019","journal-title":"J. Pediatr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss7011a1","article-title":"Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years\u2014Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018","volume":"70","author":"Maenner","year":"2021","journal-title":"MMWR Surveill. Summ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1017\/S003329171400172X","article-title":"The epidemiology and global burden of autism spectrum disorders","volume":"45","author":"Baxter","year":"2015","journal-title":"Psychol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1192\/bjp.2020.231","article-title":"Autistic traits and mental health in women with the fragile-X premutation: Maternal status versus genetic risk","volume":"218","author":"White","year":"2021","journal-title":"Br. J. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.1542\/peds.2012-0900D","article-title":"Use of psychotropic medication in children and adolescents with autism spectrum disorders","volume":"130","author":"Coury","year":"2012","journal-title":"Pediatrics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1542\/peds.2012-3774","article-title":"Psychotropic medication use and polypharmacy in children with autism spectrum disorders","volume":"132","author":"Spencer","year":"2013","journal-title":"Pediatrics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/1866-1955-6-27","article-title":"Genomic studies in fragile X premutation carriers","volume":"6","author":"Lozano","year":"2014","journal-title":"J. Neurodev. Disord."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4676","DOI":"10.1007\/s00415-022-11209-5","article-title":"Autism spectrum disorder in the Fragile X premutation state: Possible mechanisms and implications","volume":"269","author":"Aishworiya","year":"2022","journal-title":"J. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1093\/hmg\/ddp479","article-title":"Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration","volume":"19","author":"Chen","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1093\/hmg\/ddx148","article-title":"Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor\/ataxia syndrome","volume":"26","author":"Robin","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1093\/hmg\/ddr211","article-title":"Altered zinc transport disrupts mitochondrial protein processing\/import in fragile X-associated tremor\/ataxia syndrome","volume":"20","author":"Napoli","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1866-1955-6-25","article-title":"Mouse models of the fragile X premutation and fragile X-associated tremor\/ataxia syndrome","volume":"6","author":"Berman","year":"2014","journal-title":"J. Neurodev. Disord."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/WCO.0000000000000954","article-title":"Fragile X-associated tremor\/ataxia syndrome: Pathophysiology and management","volume":"34","author":"Hagerman","year":"2021","journal-title":"Curr. Opin. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"338","DOI":"10.3389\/fgene.2018.00338","article-title":"Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins","volume":"9","author":"Napoli","year":"2018","journal-title":"Front. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neuron.2012.04.009","article-title":"De novo gene disruptions in children on the autistic spectrum","volume":"74","author":"Iossifov","year":"2012","journal-title":"Neuron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss6706a1","article-title":"Prevalence of autism spectrum disorder among children aged 8 years\u2014Autism and developmental disabilities monitoring network, 11 sites, United States, 2014","volume":"67","author":"Baio","year":"2018","journal-title":"MMWR Surveill. Summ."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1017\/S0033291710000991","article-title":"IQ in children with autism spectrum disorders: Data from the Special Needs and Autism Project (SNAP)","volume":"41","author":"Charman","year":"2011","journal-title":"Psychol. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/12\/2399\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:43:24Z","timestamp":1760147004000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/12\/2399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,17]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["genes13122399"],"URL":"https:\/\/doi.org\/10.3390\/genes13122399","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,17]]}}}