PT Journal AU Hussain, SI Muhammad, N Khan, N Khan, M Fardous, F Tahir, R Yasin, M Khan, SA Saleha, S Muhammad, N Wasif, N Khan, S TI Molecular insight into CREBBP and TANGO2 variants causing intellectual disability SO The journal of gene medicine : a cross-disciplinary journal of research on the science of gene transfer and its clinical applications JI The Journal of Gene Medicine PY 2024 BP e3591 VL 26 IS 1 PU Wiley DI 10.1002/jgm.3591 WP https://macau.uni-kiel.de/receive/macau_mods_00005589 LA en DE Humans; Rubinstein-Taybi Syndrome; Rhabdomyolysis; Phenotype; Mutation; Mutation, Missense; CREB-Binding Protein; Intellectual Disability; Bioinformatics; Molecular genetics; Neurology SN 1099-498X AB 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. PI Chichester ER