{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:00Z","timestamp":1787028480333,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,13]],"date-time":"2022-08-13T00:00:00Z","timestamp":1660348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the second most common cause after Down syndrome. FXS is an X-linked disorder due to a full mutation of the CGG triplet repeat of the FMR1 gene which codes for a protein that is crucial in synaptogenesis and maintaining functions of extracellular matrix-related proteins, key for the development of normal neuronal and connective tissue including collagen. In addition to neuropsychiatric and behavioral problems, individuals with FXS show physical features suggestive of a connective tissue disorder including loose skin and joint laxity, flat feet, hernias and mitral valve prolapse. Disturbed collagen leads to hypermobility, hyperextensible skin and tissue fragility with musculoskeletal, cardiovascular, immune and other organ involvement as seen in hereditary disorders of connective tissue including Ehlers\u2013Danlos syndrome. Recently, FMR1 premutation repeat expansion or carrier status has been reported in individuals with connective tissue disorder-related symptoms. We examined a cohort of females with features of a connective tissue disorder presenting for genetic services using next-generation sequencing (NGS) of a connective tissue disorder gene panel consisting of approximately 75 genes. In those females with normal NGS testing for connective tissue disorders, the FMR1 gene was then analyzed using CGG repeat expansion studies. Three of thirty-nine females were found to have gray zone or intermediate alleles at a 1:13 ratio which was significantly higher (p &lt; 0.05) when compared with newborn females representing the general population at a 1:66 ratio. This association of connective tissue involvement in females with intermediate or gray zone alleles reported for the first time will require more studies on how the size variation may impact FMR1 gene function and protein directly or in relationship with other susceptibility genes involved in connective tissue disorders.<\/jats:p>","DOI":"10.3390\/ijms23169090","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T01:47:21Z","timestamp":1660528041000},"page":"9090","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Connective Tissue Disorders and Fragile X Molecular Status in Females: A Case Series and Review"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2911-0524","authenticated-orcid":false,"given":"Merlin G.","family":"Butler","sequence":"first","affiliation":[{"name":"Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd. MS 4015, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waheeda A.","family":"Hossain","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd. MS 4015, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Steinle","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd. MS 4015, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Gao","sequence":"additional","affiliation":[{"name":"Fulgent Genetics, 4978 Santa Anita Ave., Temple City, CA 91780, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleina","family":"Cox","sequence":"additional","affiliation":[{"name":"Fulgent Genetics, 4978 Santa Anita Ave., Temple City, CA 91780, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Niu","sequence":"additional","affiliation":[{"name":"Fulgent Genetics, 4978 Santa Anita Ave., Temple City, CA 91780, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May","family":"Quach","sequence":"additional","affiliation":[{"name":"Fulgent Genetics, 4978 Santa Anita Ave., Temple City, CA 91780, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5509-7749","authenticated-orcid":false,"given":"Olivia J.","family":"Veatch","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd. MS 4015, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,13]]},"reference":[{"key":"ref_1","first-page":"216","article-title":"Fragile X Syndrome","volume":"12","author":"McLennan","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_2","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. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1002\/ajmg.a.36511","article-title":"Epidemiology of Fragile X Syndrome: A Systematic Review and Meta-Analysis","volume":"164A","author":"Hunter","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13052-017-0355-y","article-title":"Fragile X Syndrome: A Review of Clinical and Molecular Diagnoses","volume":"43","author":"Ciaccio","year":"2017","journal-title":"Ital. J. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/cge.13469","article-title":"Fragile X Syndrome and Connective Tissue Dysregulation","volume":"95","author":"Duque","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1136\/jmedgenet-2020-107609","article-title":"Hypermobile Ehlers-Danlos Syndrome (HEDS) Phenotype in Fragile X Premutation Carriers: Case Series","volume":"59","author":"Tassanakijpanich","year":"2022","journal-title":"J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/ajmg.1320380220","article-title":"Anthropometric Comparison of Mentally Retarded Males with and without the Fragile X Syndrome","volume":"38","author":"Butler","year":"1991","journal-title":"Am. J. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1399-0004.1993.tb03863.x","article-title":"Anthropometric and Craniofacial Patterns in Mentally Retarded Males with Emphasis on the Fragile X Syndrome","volume":"44","author":"Butler","year":"1993","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/2040-2392-1-12","article-title":"Fragile X and Autism: Intertwined at the Molecular Level Leading to Targeted Treatments","volume":"1","author":"Hagerman","year":"2010","journal-title":"Mol. Autism"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.12688\/f1000research.11885.1","article-title":"Fragile X Syndrome and Fragile X-Associated Disorders","volume":"6","author":"Rajaratnam","year":"2017","journal-title":"F1000Research"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"656","DOI":"10.3389\/fpsyt.2018.00656","article-title":"Autism, Joint Hypermobility-Related Disorders and Pain","volume":"9","author":"Cohen","year":"2018","journal-title":"Front. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.c.31552","article-title":"The 2017 International Classification of the Ehlers-Danlos Syndromes","volume":"175","author":"Malfait","year":"2017","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/ajmg.a.32060","article-title":"Expanded Clinical Phenotype of Women with the FMR1 Premutation","volume":"146A","author":"Coffey","year":"2008","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/ejhg.2009.51","article-title":"Penetrance of FMR1 Premutation Associated Pathologies in Fragile X Syndrome Families","volume":"17","author":"Madrigal","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1002\/ajmg.a.35569","article-title":"Immune-Mediated Disorders among Women Carriers of Fragile X Premutation Alleles","volume":"158A","author":"Winarni","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/gim.2014.106","article-title":"Fragile X Full Mutation Expansions Are Inhibited by One or More AGG Interruptions in Premutation Carriers","volume":"17","author":"Nolin","year":"2015","journal-title":"Genet. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/s10815-020-01701-0","article-title":"Does the Presence of AGG Interruptions within the CGG Repeat Tract Have a Protective Effect on the Fertility Phenotype of Female FMR1 Premutation Carriers?","volume":"37","author":"Kirshenbaum","year":"2020","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Steinle, J., Hossain, W.A., Veatch, O.J., Strom, S.P., and Butler, M.G. (Am. J. Med. Genet. Part A, 2022). Next-generation Sequencing and Analysis of Consecutive Patients Referred for Connective Tissue Disorders, Am. J. Med. Genet. Part A, ahead of print.","DOI":"10.1002\/ajmg.a.62905"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","unstructured":"Desai, A., Connolly, J.J., March, M., Hou, C., Chiavacci, R., Kim, C., Lyon, G., Hadley, D., and Hakonarson, H. (2016). Systematic Data-Querying of Large Pediatric Biorepository Identifies Novel Ehlers-Danlos Syndrome Variant. BMC Musculoskelet. Disord., 17.","DOI":"10.1186\/s12891-016-0936-8"},{"key":"ref_21","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_22","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_23","doi-asserted-by":"crossref","first-page":"R83","DOI":"10.1093\/hmg\/ddq166","article-title":"Advances in Understanding the Molecular Basis of FXTAS","volume":"19","author":"Hagerman","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.trsl.2011.01.007","article-title":"MicroRNA, a New Paradigm for Understanding Immunoregulation, Inflammation, and Autoimmune Diseases","volume":"157","author":"Dai","year":"2011","journal-title":"Transl. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1365-2982.2008.01171.x","article-title":"Dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Irritable Bowel Syndrome","volume":"21","author":"Chang","year":"2009","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"462","DOI":"10.4161\/rna.7.4.12301","article-title":"Alternative Splicing in Multiple Sclerosis and Other Autoimmune Diseases","volume":"7","author":"Evsyukova","year":"2010","journal-title":"RNA Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1172\/JCI33680","article-title":"Impaired MicroRNA Processing Causes Corpus Luteum Insufficiency and Infertility in Mice","volume":"118","author":"Otsuka","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/ajmg.a.35833","article-title":"Fragile X AGG Analysis Provides New Risk Predictions for 45-69 Repeat Alleles","volume":"161A","author":"Nolin","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.pain.2006.04.012","article-title":"Explaining Sex Differences in Chronic Musculoskeletal Pain in a General Population","volume":"124","author":"Wijnhoven","year":"2006","journal-title":"Pain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"208","DOI":"10.5334\/tohm.233","article-title":"In the Gray Zone in the Fragile X Gene: What Are the Key Unanswered Clinical and Biological Questions?","volume":"4","author":"Hall","year":"2014","journal-title":"Tremor Other Hyperkinetic Mov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s12311-016-0809-6","article-title":"Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: A Case Series","volume":"15","author":"Debrey","year":"2016","journal-title":"Cerebellum"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"324","DOI":"10.2353\/jmoldx.2009.080173","article-title":"Screening for Expanded Alleles of the FMR1 Gene in Blood Spots from Newborn Males in a Spanish Population","volume":"11","author":"Walichiewicz","year":"2009","journal-title":"J. Mol. Diagn."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1002\/mds.28086","article-title":"Fragile X Gray Zone Alleles Are Associated with Signs of Parkinsonism and Earlier Death","volume":"35","author":"Hall","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/978-1-4614-5434-2_6","article-title":"Unstable Mutations in the FMR1 Gene and the Phenotypes","volume":"769","author":"Loesch","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/ajmg.a.38504","article-title":"Rare FMR1 Gene Mutations Causing Fragile X Syndrome: A Review","volume":"176","author":"Sitzmann","year":"2018","journal-title":"Am. J. Med. Genet. A"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9090\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:08:24Z","timestamp":1760141304000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9090"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,13]]},"references-count":35,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23169090"],"URL":"https:\/\/doi.org\/10.3390\/ijms23169090","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,13]]}}}