{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:18:03Z","timestamp":1787901483750,"version":"build-2784847793"},"reference-count":44,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Marfan syndrome (MFS) is a rare connective tissue disorder characterized by involvement of the cardiovascular, ocular, and musculoskeletal systems. Pathogenic variants in\n                    <jats:italic>FBN1<\/jats:italic>\n                    cause most of the MFS cases; however, intellectual disability (ID) is rarely observed. A non\u2010consanguineous Pakistani family with four affected individuals was recruited. Physical examinations, echocardiography, and doppler ultrasound were performed as part of the clinical assessment. Exome sequencing was conducted on the index patient, and Sanger sequencing was performed for the entire family. ID was the primary symptom in all the affected individuals. A detailed examination showed that all affected individuals and their affected mother were tall, had long limbs, craniofacial abnormalities, and exhibited low IQ, aggressive, and hyperactive behaviors. Heart defects, such as atrial septal defects and pulmonary hypertension, were observed in one affected individual and her mother. Genetic analysis identified two rare missense variants in\n                    <jats:italic>FBN1,<\/jats:italic>\n                    c.1552G&gt;A (p.Gly518Arg) and c.3046A&gt;G (p.Thr1016Ala), both predicted to be deleterious. The p.Gly518Arg variant is predicted to be likely pathogenic, while the p.Thr1016Ala variant is of uncertain significance. Notably, these variants were found in two affected individuals in a compound heterozygous state, correlating with more severe symptoms. Each variant alone, seen in the two patients, is associated with milder symptoms, indicating incomplete penetrance. In conclusion, this study identified rare heterozygous missense variants in\n                    <jats:italic>FBN1<\/jats:italic>\n                    , suggesting a potential connection between neurodevelopmental outcomes and variants in\n                    <jats:italic>FBN1<\/jats:italic>\n                    . However, further research is needed to clarify the role of\n                    <jats:italic>FBN1<\/jats:italic>\n                    in ID.\n                  <\/jats:p>","DOI":"10.1002\/ajmga.70038","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T03:57:08Z","timestamp":1767585428000},"page":"1021-1035","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Marfan Syndrome Associated With Intellectual Disability and Behavioral Anomalies: Further Evidence for the Effect of Compound Heterozygous Variants in\n                    <scp>\n                      <i>FBN1<\/i>\n                    <\/scp>\n                    on Phenotypic Severity"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6947-6339","authenticated-orcid":false,"given":"Azmatullah","family":"Khan","sequence":"first","affiliation":[{"name":"Human Genetics Program, Department of Zoology Faculty of Biological Sciences, Quaid\u2010i\u2010Azam University  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naseebullah","family":"Kakar","sequence":"additional","affiliation":[{"name":"Department of Biotechnology FLS&amp;I, BUITEMS  Quetta Pakistan"},{"name":"Institut f\u00fcr Humangenetik Universit\u00e4tsklinikum Schleswig\u2010Holstein, University of L\u00fcbeck and University of Kiel  L\u00fcbeck Germany"},{"name":"Institute of Human Genetics, University of Regensburg &amp; Universit\u00e4tsklinikum Regensburg  Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainullah","family":"Kakar","sequence":"additional","affiliation":[{"name":"Bolan Medical Complex Hospital  Quetta Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Spielmann","sequence":"additional","affiliation":[{"name":"Department of Biotechnology FLS&amp;I, BUITEMS  Quetta Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5563-9053","authenticated-orcid":false,"given":"Sajid","family":"Malik","sequence":"additional","affiliation":[{"name":"Human Genetics Program, Department of Zoology Faculty of Biological Sciences, Quaid\u2010i\u2010Azam University  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31202"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.12659\/AJCR.930824"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-103996"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-024-07625-2"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2013.10036"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1244983"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12094"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2010.30"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.21.3.173"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10249"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201865"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091217415612701"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0369-8"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22105"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-73969-2"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-024-02718-6"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90069-Q"},{"issue":"6","key":"e_1_2_11_19_1","first-page":"1083","article-title":"A Compound\u2010Heterozygous Marfan Patient: Two Defective Fibrillin Alleles Result in a Lethal Phenotype","volume":"55","author":"Karttunen L.","year":"1994","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.2.133"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-018-9491-8"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics13132284"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2022-059083"},{"key":"e_1_2_11_24_1","unstructured":"Marzin P. V.Cormier\u2010Daire andE.Tsilou.2020.Weill\u2010Marchesani Syndrome."},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.15586\/jcbmr.2015.10"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1116"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-022-00338-w"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/apa.12072"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2016.6"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-021-01045-3"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.51.1.481"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197904053001406"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1988.tb10679.x"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.12.018"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.2106\/00004623-199506000-00007"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/apa.16307"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3126\/jnhls.v2i1.55802"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.124.1.171"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36157"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/scd.12018"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2008.11.004"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21131"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22977"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm035"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmga.70038","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmga.70038","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmga.70038","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T06:49:08Z","timestamp":1787899748000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmga.70038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,4]]},"references-count":44,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/ajmga.70038"],"URL":"https:\/\/doi.org\/10.1002\/ajmga.70038","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,4]]},"assertion":[{"value":"2025-02-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}