{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T19:09:51Z","timestamp":1775070591333,"version":"3.50.1"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004681","name":"Higher Education Commission, Pakistan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004681","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Intellectual disability (ID) can be associated with different syndromes such as Rubinstein\u2010Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB\u2010binding protein (<jats:italic>CREBBP<\/jats:italic>) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2\u2010related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Clinicians need more clinical and genetic evidence to detect and comprehend the phenotypic spectrum of this disorder.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Exome sequencing was used to identify the disease\u2010causing variants in two affected families A and B from District Kohat and District Karak, Khyber Pakhtunkhwa. Affected individuals from both families presented symptoms of ID, developmental delay and behavioral abnormalities. The validation and co\u2010segregation analysis of the filtered variant was carried out using Sanger sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A&gt;G; NP_004371.2: p.Lys1524Arg) in the <jats:italic>CREBBP<\/jats:italic> gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605\u2009+\u20091G&gt;A) in the <jats:italic>TANGO2<\/jats:italic> gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild\u2010type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype\u2013phenotype associations.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3591","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T09:38:25Z","timestamp":1695029905000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular insight into <i>CREBBP<\/i> and <i>TANGO2<\/i> variants causing intellectual disability"],"prefix":"10.1002","volume":"26","author":[{"given":"Syeda Iqra","family":"Hussain","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazif","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niamatullah","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mobeen","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fardous","family":"Fardous","sequence":"additional","affiliation":[{"name":"Department of Medical Lab Technology Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raheel","family":"Tahir","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Yasin","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sher Alam","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamim","family":"Saleha","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noor","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3455-8833","authenticated-orcid":false,"given":"Naveed","family":"Wasif","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Ulm University and Ulm University Medical Center  Ulm Germany"},{"name":"Institute of Human Genetics University Hospital Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saadullah","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetic Engineering Kohat University of Science and Technology (KUST)  Kohat Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1168307"},{"key":"e_1_2_11_3_1","unstructured":"BoatTF WuJ.Committee to evaluate the supplemental security income disability program for children with mental disorders. 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