000K utf8 1100 $c2024 1500 eng 2050 urn:nbn:de:gbv:8:3-2025-00068-9 2051 10.1002/jgm.3591 3000 Hussain, Syeda Iqra 3010 Fardous, Fardous 3010 Khan, Mobeen 3010 Khan, Niamatullah 3010 Khan, Saadullah 3010 Khan, Sher Alam 3010 Muhammad, Nazif 3010 Muhammad, Noor 3010 Saleha, Shamim 3010 Tahir, Raheel 3010 Wasif, Naveed 3010 Yasin, Muhammad 4000 Molecular insight into CREBBP and TANGO2 variants causing intellectual disability$hWiley [Hussain, Syeda Iqra] 4030 $nWiley 4209 Background Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB-binding protein (CREBBP) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2-related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Results In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A>G; NP_004371.2: p.Lys1524Arg) in the CREBBP gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605 + 1G>A) in the TANGO2 gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild-type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function. Conclusions RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype-phenotype associations. 4950 https://doi.org/10.1002/jgm.3591$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:gbv:8:3-2025-00068-9$xR$3Volltext$534 4961 https://macau.uni-kiel.de/receive/macau_mods_00005589 5051 610 5550 Bioinformatics 5550 CREB-Binding Protein 5550 Humans 5550 Intellectual Disability 5550 Molecular genetics 5550 Mutation 5550 Mutation, Missense 5550 Neurology 5550 Phenotype 5550 Rhabdomyolysis 5550 Rubinstein-Taybi Syndrome