Molecular insight into CREBBP and TANGO2 variants causing intellectual disability

Area of Science:

• Genetics
• Neuroscience
• Rare Diseases

Background:

• Intellectual disability (ID) encompasses various genetic syndromes like Rubinstein-Taybi syndrome (RSTS) and metabolic disorders.
• RSTS is linked to CREBBP gene mutations, characterized by developmental delays, distinct physical features, and malignancy risk.
• TANGO2-related metabolic encephalopathy and arrhythmia (TRMEA) presents with recurrent crises, hypoglycemia, and neurodegeneration.

Purpose of the Study:

• To identify disease-causing genetic variants in families with unexplained intellectual disability.
• To expand the understanding of genotype-phenotype correlations in rare genetic disorders.

Main Methods:

• Whole exome sequencing was employed to detect causative variants in two families presenting with ID.
• Sanger sequencing was utilized for validation and co-segregation analysis of identified variants.
• In silico tools were used to analyze the predicted impact of variants on protein structure and function.

Main Results:

• A novel missense variant in the CREBBP gene was identified in Family A, associated with RSTS-like features.
• A splice site variant in the TANGO2 gene was found in Family B, linked to TRMEA.
• Sanger sequencing confirmed the segregation of both variants with ID in the respective families, and in silico analysis suggested altered CREBBP protein structure.

Conclusions:

• The study identified novel genetic variants contributing to ID in two rare disorders, RSTS and TRMEA.
• Further multicenter studies are crucial for a comprehensive understanding of clinical phenotypes and genotype-phenotype associations.
• Expanding genetic and clinical evidence is essential for accurate diagnosis and management of these rare conditions.